5-heteroarylamino-6-oxy-substituted 3(2H)-pyridazinones

ABSTRACT

A compound of the formula, ##STR1## or its pharmaceutically acceptable salt, and its preparation process and pharmaceutical compositions characterized by containing these compounds as effective ingredients. 
     These compounds have strong antithrombotic activity, cardiotonic activity, vasodilator activity and anti-SRS-A activity, and are useful as prophylactic or therapeutic agents for various thrombotic affections, congestive heart failure, hypertension, asthma, immediate type allergy diseases and the like.

This is a division of application Ser. No. 07/768,182, filed on Oct. 16, 1991, U.S. Pat. No. 5,202,323.

TECHNICAL FIELD

The present invention relates to novel 3(2H)-pyridazinone derivatives and their pharmaceutically acceptable salts having an inhibitory activity of platelet aggregation, a cardiotonic activity, a vasodilating activity and an anti-SRS-A activity, processes for their preparation and pharmaceutical compositions containing them as active ingredients.

BACKGROUND ART

1) Field of anti-thrombotic agent

It is known that platelet aggregation plays an important role for thrombus formation in connection with a disease state. Various thrombotic diseases caused by thrombus formation mainly include cerebral thrombosis, pulmonal thrombosis, myocardial infarction, angina pectoris, occlusion of peripheral artery and the like, and all of these diseases require development for useful drugs. As a prophylactic or therapeutic drug, an anti-thrombotic agent having an inhibitory activity of platelet aggregation draws public tension. Heretofore, the effect of aspirin has been widely studied, and more recently ticlopidine and cilostazol have been clinically developed. However, a more strongly effective drug is demanded in respect of its effects.

In addition to the above-mentioned various thrombotic diseases, there are enumerated various diseases in relation to platelets. Examples for these diseases include nephritis, cancer cell metastasis and the like, and recently various studies have been conducted with regard to prophylactic or therapeutic effects for these diseases achieved mainly by an anti-thrombotic agent having an activity for controlling platelet function ("Journal of Royal College of Physicians", Vol. 7, No. 1, p. 5-18, 1972; "Japan Clinics (Nihon Rinsho)", Vol. 4, No. 6, p. 130-136, 1988; Anticancer Research, Vol 6, p. 543-548, 1986).

2) Field of cardiotonic agent

A cardiotonic agent to enhance myocardial contractive force have been used as a therapeutic drug for congestive heart failure from old times. However, conventional cardiotonic agents such as cardiac glycosides represented by digitalis, aminophylline and catecholamines have strong side effects, and therefore drugs such as milrinone and denopamine are recently clinically developed.

3) Field of vasodilator

There are many known vasodilators, but at present there are few drugs which have beneficial pharmacologic properties for circulatory system such as a satisfactory inhibitory activity of platelet aggregation.

4) Field of anti-SRS-A agent

SRS-A (Slow Reacting Substances of Anaphylaxis) is a chemical mediator released together with histamine, etc. by an allergic reaction and has pharmacological activity to cause a strong and prolonged contraction of tracheal smooth muscle. Their existence has long been known from such a phenomenal aspect.

It was found in 1979 that SRS-A itself is a mixture of leukotriene C₄ (hereinafter referred to as LTC₄), leukotriene D₄ (hereinafter referred to as LTD₄) and leukotriene E₄ (hereinafter referred to as LTE₄) [generally called peptide leukotriene].

Extensive researches have been conducted on SRS-A for its relationship with a disease state. As a result, the relationship of SRS-A with immediate type allergic diseases such as bronchial asthma, allergic rhinitis, urticaria and hay fever, has become clear.

Further, the relationship of SRS-A with various inflammatory diseases, ischemic heart diseases, etc., has been suggested.

Therefore, a compound which exhibits inhibition against SRS-A, is expected to be useful as a prophylactic or therapeutic drug against the disorders caused by either LTC₄, LTD₄ or LTE₄, or by a mixture thereof.

As the SRS-A antagonists, many medicinal substances have been reported. ("Drugs of the Future", Vol. 12, p. 453-474 (1987); "Annual Reports in Medicinal Chemistry", Vol. 22, p. 73-84 (1987) and "Annual Reviews in Pharmacological Toxicology", Vol. 29, p. 123-143 (1989)).

However, no instance of their practical clinical application has been reported.

Now, the relationship of 6-ω-substituted alkyloxy3(2H)-pyridazinones of the formula [I] and their pharmaceutically acceptable salts thereof according to the present invention with compounds disclosed in published references will be described.

(a) German Laid Open Patent Application No. 1,670,169 (hereinafter referred to as reference (a)) discloses 3(2H)-pyridazinones having hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic group at 2-position, chlorine or bromine at 4-position, an aralkylamino group at 5-position, and chlorine, bromine, a hydroxy or C₁ -C₄ alkoxy group at 6-position.

This reference (a) discloses a process for the synthesis of 3(2H)-pyridazinone derivatives, their application to agricultural chemicals, their application as intermediates for medicines or dyestuffs, or their application as intermediates for various compounds. However, no mention is made to their pharmacological activities, and no specific examples are given for such compounds. Further, such compounds are not specifically described.

(b) Japanese Unexamined Patent Publication No. 183675/1983 (hereinafter referred to as reference (b)) discloses 3(2H)-pyridazinone derivatives having a lower alkyl group at the 2-position, a hydrogen atom at the 4-position, a substituted or non-substituted anilino group at the 5-position and a hydroxyl group or a lower alkoxy group at the 6-position.

The 3(2H)-pyridazinone derivatives are disclosed to have analgesic action, anti-inflammatory action, anti-allergic action and anti-rheumatic action, but there is no disclosure concerning pharmacological activities.

(c) Japanese Unexamined Patent Publication No. 30187/1988, U.S. Pat. No. 4,978,665, European Laid Open Patent Publication No. 0275997 (hereinafter referred to as reference (c)) discloses 6-substituted alkoxy-5-substituted benzylamino-3(2H)-pyridazinone derivatives and their use as an anti-SRS-A agent, which are relatively similar to the compounds of the present invention.

DISCLOSURE OF THE INVENTION

As the result of the extensive study, the present inventors have discovered that the 3(2H)-pyridazinone derivatives and their pharmaceutically acceptable salts of the present invention, which are different from any of the compounds disclosed in the above references (a)-(c), are excellent compounds for anti-thrombotic agents, cardiotonic agents, vasodilators and/or anti-SRS-A agents, and that they can be active ingredients of prophylactic or therapeutic drugs for the above-mentioned various thrombotic diseases, congestive heart failure, hypertension and/or asthma or immediate type allergy diseases. On the basis of this discovery, the present invention has been accomplished.

That is, the present invention relates to a 3(2H)-pyridazinone derivative and its pharmaceutically acceptable salt, a process for producing the same and a pharmaceutical composition containing the same as an active ingredient, the 3(2H)-pyridazinone derivative being represented by the general formula [I], ##STR2## (wherein R¹ is a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₄ alkenyl group or (CH₂)_(n) CO₂ R⁵ (n is an integer of from 1 to 4, R⁵ is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group);

R² is A¹ --Y¹ (A¹ is a straight chained or branched C₁ -C₁₂ alkylene group, Y¹ is CO₂ R⁵ (R⁵ is as defined above), a cyano group, OR⁶ (R⁶ is a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group or a phenyl group), or a thienyl or pyridyl group which may be substituted at any position, ##STR3## (R⁷ and R⁸ are respectively and independently a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group, a phenyl group or a thiazolyl or thiadiazolyl group which may be substituted at any position, or R⁷ and R⁸ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained or branched C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom), ##STR4## (R⁵ is as defined above, R⁹ is a straight chained or branched C₁ -C₄ alkyl group or a phenyl group which may be substituted with a straight chained or branched C₁ -C₄ alkyl group or a halogen atom), ##STR5## (R¹⁰ and R¹¹ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₁ -C₄ acylamino group, OR⁵ (R⁵ is as defined above), NHSO₂ R⁹ (R⁹ is as defined above) or S(O)_(m) --R¹² (m is an integer of from 0 to 2 and R¹² is a straight chained or branched C₁ -C₄ alkyl group), provided that R¹⁰ and R¹¹ are not hydrogen atoms at the same time), ##STR6## (R¹³ is a hydrogen atom, R¹⁴ is a phenyl group, or R¹³ and R¹⁴ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group), ##STR7## (R¹⁵ is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group, R¹⁶ is a straight chained or branched C₁ -C₄ alkyl group, or R¹⁵ and R¹⁶ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group), ##STR8## (R¹⁷ and R¹⁸ are respectively and independently a straight chained or branched C₁ -C₄ alkyl group, or R¹⁷ and R¹⁸ together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group), ##STR9## (l is 1 or 2, k is an integer of from 0 to 3, and R¹⁹ is a hydrogen atom or a halogen atom), or ##STR10## ); or R² is A² --Y² (A² is a C₂ -C₁₀ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon, and Y² is a phenyl group);

R³ and R⁴ are respectively and independently a hydrogen atom or a straight chained or branched C₁ -C₃ alkyl group;

X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; and

Ar is ##STR11## [j is 0 or 1 and R²⁰ is a hydrogen atom, a halogen atom or OR¹² (R¹² is as defined above)], ##STR12## (Z¹ is an oxygen atom or a sulfur atom), ##STR13## [R²¹ is a hydrogen atom or OR⁵ (R⁵ is as defined above)], or ##STR14## [Z² and Z³ are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, OR²² (R²² is a hydrogen atom or a straight chained or branched C₁ -C₈ alkyl group), or

O--A¹ --Y³ (A¹ is as defined above and Y³ is a phenyl group which may be substituted with a straight chained or branched C₁ -C₄ alkyl group or a halogen atom, CO₂ R⁵, or ##STR15## (R⁵, R⁷ and R⁸ are as defined above)), or Z² and Z³ together with a benzene ring, form ##STR16## (W forms a C₁ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group)]); and a pharmaceutically acceptable salt thereof.

R¹, R², R³, R⁴, X and Ar in the above general formula [I] representing the compound of the present invention are explained hereinafter.

Examples of R¹ include, a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a 2-propenyl group, a 2-methyl-2-propenyl group, a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxylbutyl group, a methoxycarbonylmethyl group, a 2-methoxycarbonylethyl group, a 3-methoxycarbonylpropyl group, a 4-methoxycarbonyl butyl group, an ethoxycarbonylmethyl group, a 2-ethoxycarbonylethyl group, a 3-ethoxycarbonylpropyl group, a 4-ethoxycarbonylbutyl group, an n-propoxycarbonylmethyl group, an i-propoxycarbonylmethyl group, a 2-n-propoxycarbonylethyl, a 2-i-propoxycarbonylethyl group, a 3-n-propoxycarbonylpropyl group, a 3-i-propoxycarbonylpropyl group, a 4-n-propoxycarbonylbutyl group, a 4-i-propoxycarbonylbutyl group, an n-butoxycarbonylmethyl group, an i-butoxycarbonylmethyl group, a seo-butoxycarbonylmethyl group, a t-butoxycarbonylmethyl group, a 2-n-butoxycarbonylethyl group, a 2-i-butoxycarbonylethyl group, a 2-sec-butoxycarbonylethyl group, a 2-t-butoxycarbonylethyl group, a 3-n-butoxycarbonylpropyl group, a 3-i-butoxycarbonylpropyl group, a 3-sec-butoxycarbonylpropyl group, a 3-t-butoxycarbonylpropyl group, a 4-n-butoxycarbonylbutyl group, a 4-i-butoxycarbonylbutyl group, a 4-sec-butoxycarbonylbutyl group, a 4-t-butoxycarbonylbutyl group and the like, preferably a hydrogen atom, an ethyl group and an i-propyl group, and more preferably a hydrogen atom.

Examples of R² include A¹ --Y¹ or A² --Y² wherein A¹ is a straight chained or branched C₁ -C₁₂ alkylene group and A² is a C₂ -C₁₀ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon atom.

Examples of Y¹ include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a sec-butoxycarbonyl group, a t-butoxycarbonyl group, a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a cyano group, a hydroxyl group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, a phenoxy group, a carbamoyl group, an N-methylaminocarbonyl group, an N-ethylaminocarbonyl group, an N-n-propylaminocarbonyl group, an N-i-propylaminocarbonyl group, an N-n-butylaminocarbonyl group, an N-i-butylaminocarbonyl group, an N-sec-butylaminocarbonyl group, an N-t-butylaminocarbonyl group, an N-cyclopropylaminocarbonyl group, an N-cyclobutylaminocarbonyl group, an N-cyclopentylaminocarbonyl group, an N-cyclohexylaminocarbonyl group, an N-cycloheptylaminocarbonyl group, an N-cyclooctylaminocarbonyl group, an N-phenylaminocarbonyl group, an N-2-thiazolylaminocarbonyl group, an N-4-thiazolylaminocarbonyl group, an N-5-thiazolylaminocarbonyl group, an N-2-thiadiazolylaminocarbonyl group, an N-5-thiadiazolylaminocarbonyl group, a 1-aziridinocarbonyl group, a 1-azetidinocarbonyl group, a 1-pyrrolidinocarbonyl group, a 1-piperidinocarbonyl group, a 1-homopiperidinocarbonyl group, a 1-(2,5-dimethyl)pyrrolidinocarbonyl group, a 1-(2,6-dimethyl)piperidinocarbonyl group, a 1-(3-phenyl)pyrrolidinocarbonyl group, a 1-(4-phenyl)piperidinocarbonyl group, an N-methysulfonylamino group, an N-ethylsulfonylamino group, an N-n-propylsulfonyl group, an N-i-propylsulfonylamino group, an N-n-butylsulfonylamino group, an N-i-butylsulfonylamino group, an N-sec-butylsulfonylamino group, an N-t-butylsulfonylamino group, a 1-morpholinocarbonyl group, an N-phenylsulfonylamino group, an N-substituted phenylsulfonylamino group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a substituted phenyl group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a formylamino group, an acetylamino group, a propionylamino group, a butyrylamino group, a methylsulfonylamino group, an ethylsulfonylamino group, an N-n-propylsulfonylamino group, an N-i-propylsulfonylamino group, an N-n-butylsulfonylamino group, an N-i-butylsulfonylamino group, an N-sec-butylsulfonylamino group, an N-t-butylsulfonylamino group, an N-phenylsulfonylamino group, a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a t-butoxy group, an N-substituted phenylsulfonylamino group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, a sec-butylthio group, a t-butylthio group, a methylsulfoxy group, an ethylsulfoxy group, an n-propylsulfoxy group, an i-propylsulfoxy group, an n-butylsulfoxy group, an i-butylsulfoxy group, a sec-butylsulfoxy group, a t-butylsulfoxy group, a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i-butylsulfonyl group, a sec-butylsulfonyl group, or a t-butylsulfonyl group on the ortho-, meta- or para-position of the benzene ring), an N-phenylcarbonylamino group, a 1-(2-oxo)azetidinyl group, a 1-(2-oxo)pyrrolidinyl group, a 1-(2-oxo)piperidinyl group, a 1-(2-oxo)homopiperidinyl group, a 1-(2-oxo-3,3-dimethyl)pyrrolidinyl group, a 1-(2-oxo-5,5-dimethyl)pyrrolidinyl group, an N-methoxycarbonylamino group, an N-ethoxycarbonylamino group, an N-n-propoxycarbonylamino group, an N-i-propoxycarbonylamino group, an N-n-butoxycarbonylamino group, an N-i-butoxycarbonylamino group, an N-sec-butoxycarbonylamino group, an N-t-butoxycarbonylamino group, a 3-(2-oxo)oxazolidinyl group, a 3-(2-oxo-5,5-dimethyl)oxazolidinyl group, a 3-(2-oxo-4,4-diethyl)oxazolidinyl group, a 3-(2-oxo-5,5-diethyl)oxazolidinyl group, an N,N-di-substituted amino group (having an optional combination of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group and a t-butyl group), a 1-azetidino group, a 1-pyrrolidino group, a 1-piperidino group, a 1-(2,5-dimethyl)pyrrolidino group, a 1-(3,4-dimethyl)pyrrolidino group, a 1-(4,4-dimethyl)piperidino group, a 1-(4-phenylmethyl)piperadino group, 1-(4-diphenylmethyl)piperadino group, a 1-(4-substituted phenylmethyl)piperadinyl or 1-(4-di-substituted phenylmethyl)piperadinyl group (which is substituted with a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), a phenylaminocarboxyl group, an N,N-di-substituted aminocarbonyl group (having an optional combination of a linear or cyclic alkyl group, a phenyl group, a thiazolyl group or a thiadiazolyl group on the above described N-substituted aminocarbonyl groups), N-alkyl-N-phenylsulfonylamino, N,N-dialkylsulfonylamino or N-alkyl-N-alkoxycarbonylamino groups (having a linear or branched C₁ -C₄ alkyl substituent on the nitrogen atom of the above described N-phenylsulfonylamino, N-alkylsulfonylamino or N-alkoxycarbonylamino groups), di-substituted phenyl groups (which are substituted on the ortho-, meta- or para-position of the benzene ring with an optional combination of a halogen atom, a linear alkyl group, an acylamino group, a hydroxy group, an alkoxy group, an N-phenylsulfonylamino group, an N-alkylsulfonylamino group, a linear alkylthio group and a linear alkylsulfonyl group on the above described substituted phenyl groups), and the like.

Examples of Y² include a phenyl group.

Examples of R³ and R⁴ include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group and an i-propyl group, preferably a hydrogen atom.

Examples of X include a hydrogen atom, a chlorine atom, a bromine atom and a cyano group, preferably each substituent other than a hydrogen atom.

Examples of Ar include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a substituted 2-pyridyl group, 3-pyridyl or 4-pyridyl (which is substituted with a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group on the 2-, 3-, 4-, 5- or 6-position of the pyridine ring), an N-oxidopyrizyl group corresponding to the above described pyridyl or substituted pyridyl group, a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a 1-naphthyl group, a 2-naphthyl group, a 1-naphthyl or 2-naphthyl group (which is substituted with a hydroxy group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group or a t-butoxy group on an optional position of the naphthalene ring) or substituted phenyl groups having the following one or two substituents in optional combination at an optional position. Examples of the substituents include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a hydroxy group, an alkoxy group (having a linear or branched C₁ -C₈ alkyl group), a dioxyemthylene, 1,2-dioxyethylene or 1,3-dioxypropylene group (which comprises adjacent two substituents joined together), or an O--A¹ --Y³ group. A¹ is a linear or branched C₁ -C₁₀ alkylene group, Y³ is a phenyl group, a substituted phenyl group (which is substituted with a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom on the ortho-, meta- or para-position of the benzene ring), or the above-mentioned (with regard to Y¹) carboxyl, alkoxycarbonyl, 1-cycloaminocarbonyl, 1-morpholinocarbonyl, or carbamoyl, N-substituted or N,N-disubstituted aminocarbonyl group (having on a nitrogen atom an optional combination of two substituents of a hydrogen atom, a linear, branched or cyclic alkyl group, a phenyl group, a thiazolyl group and a thiadiazolyl group). Preferable examples include a 3-pyridyl group or 3-substituted-4-methoxyphenyl type group, but the present invention should not be limited to these examples.

In the above description "n", "i", "sec" and "t" respectively stand for "normal", "iso", "secondary" and "tertiary".

Preferable compounds of the compounds having the general formula [I] of the present invention are represented by the following general formula [IC], ##STR17## {wherein R^(1c) is a hydrogen atom; R^(2') is A¹ --Y^(3') [A¹ is a straight chained or branched C₁ -C₁₂ alkylene group, Y^(3') is CO₂ R^(5') (R^(5') is a straight chained or branched C₁₋₄ alkyl group), ##STR18## (R^(7') and R^(8') are respectively and independently a hydrogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group or a phenyl group, R^(7') and R^(8') together form a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom), ##STR19## (R⁵ is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group, R^(9') is a phenyl group which may be substituted with a straight chained or branched C₁ -C₄ alkyl group or a halogen atom), ##STR20## (R^(10') and R^(11') are respectively and independently a hydrogen atom, a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, a C₁ -C₄ acylamino group, OR⁵ (R⁵ is as defined above), NHSO₂ R^(9") (R^(9") is a straight chained or branched C₁ -C₄ alkyl group) or S(O)_(m) --R¹² (m is 0 or 2 and R¹² is a straight chained or branched C₁ -C₄ alkyl group), provided that R^(10') and R^(11') are not hydrogen atoms at the same time), ##STR21## (R^(13') is a hydrogen atom, R^(14') is a phenyl group, or R^(13') and R^(14') together form a C₂ -C₅ alkylene group), ##STR22## (R^(15') is a hydrogen atom or a straight chained or branched C₁ -C₄ alkyl group, R^(16') is a straight chained or branched C₁ -C₄ alkyl group, or R^(15') and R^(16') together form a C₂ -C₆ alkylene group), ##STR23## (R^(17') and R^(18') are respectively and independently a straight chained or branched C₁ -C₄ alkyl group, or R^(17') and R^(18') together form a C₂ -C₆ alkylene group), ##STR24## (1 is 1 or 2, and R¹⁹ is a hydrogen atom or a halogen atom), or ##STR25## ]; or R² is A² -Y² (A² is a C₂ -C₈ alkylene group which may be substituted with a straight chained C₁ -C₃ alkyl group, except for the case that a carbon chain connecting an oxygen atom with Y² has one carbon, and Y² is a phenyl group);

Xc' is a chlorine atom, a bromine atom, or a cyano group; and

Ar' is a 3-pyridyl group, or ##STR26## [Z³ is a halogen atom, a straight chained or branched C₁ -C₄ alkyl group, OR²² (R²² is a hydrogen atom or a straight chained or branched C₁₋₈ alkyl group) or O--A³ --Y³ (A³ is a C₁ -C₄ alkylene group, Y³ is a phenyl group, CO₂ R^(5'), ##STR27## (R^(5'), R^(7') and R^(8') are as defined above))]}.

The compounds of the general formula [I] of the present invention include optical isomers and stereoisomers based on from 1 to 6 asymmetric carbon atoms.

Hereinafter, typical compounds of the 3(2H)-pyridazinone derivatives of the general formula [I] and pharmaceutically acceptable salts thereof of the present invention are illustrated in the following Table 1, but the present invention should not be limited thereto.

In Table 1, "n" stands for normal, "i" stands for iso, "sec" stands for secondary, "Me" stands for a methyl group, "Et" stands for an ethyl group, "Pr" stands for a propyl group, "Bu" stands for a butyl group, "Pen" stands for a pentyl group, "Hex" stands for a hexyl group, "Hep" stands for a heptyl group, "Oct" stands for an octyl group, "Ac" stands for an acetyl group, and "Ph" stands for a phenyl group.

Q1-Q108 in Table I are groups represented by the following formulas. ##STR28##

                                      TABLE I                                      __________________________________________________________________________     No.                                                                               R.sup.1                                                                              R.sup.2         R.sup.3                                                                           R.sup.4                                                                           X  Ar                                           __________________________________________________________________________      1 H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                   H  H  Cl Q23                                           2 H     (CH.sub.2).sub.5 CO.sub.2 H                                                                    H  H  Cl Q23                                           3 H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                   H  H  Cl Q76                                           4 H     (CH.sub.2).sub.5 CO.sub.2 H                                                                    H  H  Cl Q76                                           5 H     CH.sub.2 CO.sub.2 Et                                                                           H  H  Cl Q76                                           6 H     CH.sub.2 CO.sub.2 H                                                                            H  H  Cl Q76                                           7 H     CH.sub.2 CO.sub.2 Me                                                                           H  H  Cl Q76.HCl                                       8 H     (CH.sub.2).sub.5 CONHMe                                                                        H  H  Cl Q23                                           9 H     (CH.sub.2).sub.5 CONMe.sub.2                                                                   H  H  Cl Q23                                           10                                                                               H     (CH.sub.2).sub.5 CONH.sub. 2                                                                   H  H  Cl Q23                                           11                                                                               H     (CH.sub.2).sub.5 COQ87                                                                         H  H  Cl Q23                                           12                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                   H  H  Cl Q23                                           13                                                                               H     (CH.sub.2).sub.5 CON(Me)Q1                                                                     H  H  Cl Q23                                           14                                                                               H     (CH.sub.2).sub.3 CO.sub.2 Et                                                                   H  H  Cl Q23                                           15                                                                               H     (CH.sub.2).sub.3 CO.sub.2 H                                                                    H  H  Cl Q23                                           16                                                                               H     (CH.sub.2).sub.3 CONMe.sub.2                                                                   H  H  Cl Q23                                           17                                                                               H     (CH.sub.2).sub.3 CONEt.sub.2                                                                   H  H  Cl Q23                                           18                                                                               H     (CH.sub.2).sub.3 COQ87                                                                         H  H  Cl Q23                                           19                                                                               H     CH.sub.2 CO.sub.2 Et                                                                           H  H  Cl Q23                                           20                                                                               H     CH.sub.2 CO.sub.2 H                                                                            H  H  Cl Q23                                           21                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 Q2                                                                 H  H  Cl Q23                                           22                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 Q2                                                                 H  H  Cl Q76                                           23                                                                               H     (CH.sub.2).sub.2 NHSO.sub.2 Ph                                                                 H  H  Cl Q23                                           24                                                                               H     (CH.sub.2).sub.2 NHSO.sub.2 Ph                                                                 H  H  Cl Q76                                           25                                                                               H     (CH.sub.2).sub.5 CON-n-Pr.sub. 2                                                               H  H  Cl Q23                                           26                                                                               H     (CH.sub.2).sub.5 COQ83                                                                         H  H  Cl Q23                                           27                                                                               H     (CH.sub.2).sub.5 COQ82                                                                         H  H  Cl Q23                                           28                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                   H  H  Cl Q76                                           29                                                                               H     (CH.sub.2).sub.5 CONMe.sub.2                                                                   H  H  Cl Q76                                           30                                                                               H     (CH.sub.2).sub.7 CO.sub.2 Me                                                                   H  H  Cl Q23                                           31                                                                               H     (CH.sub.2).sub.7 CO.sub.2 H                                                                    H  H  Cl Q23                                           32                                                                               H     (CH.sub.2).sub.5 COQ82                                                                         H  H  Cl Q76                                           33                                                                               H     (CH.sub.2).sub.5 COQ83                                                                         H  H  Cl Q76                                           34                                                                               H     (CH.sub.2).sub.7 CONMe.sub.2                                                                   H  H  Cl Q23                                           35                                                                               H     (CH.sub.2).sub.7 CONEt.sub.2                                                                   H  H  Cl Q23                                           36                                                                               H     (CH.sub.2).sub.7 CON-n-Pr.sub.2                                                                H  H  Cl Q23                                           37                                                                               H     (CH.sub.2).sub.7 COQ82                                                                         H  H  Cl Q23                                           38                                                                               H     (CH.sub.2).sub.7 COQ83                                                                         H  H  Cl Q23                                           39                                                                               H     (CH.sub.2).sub.7 COQ87                                                                         H  H  Cl Q23                                           40                                                                               H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                   H  H  Cl Q16                                           41                                                                               H     (CH.sub.2).sub.5 CO.sub.2 Me                                                                   H  H  Br Q23                                           42                                                                               H     (CH.sub.2).sub.5 CO.sub.2 H                                                                    H  H  Br Q23                                           43                                                                               H     (CH.sub.2).sub.5 CONMe.sub.2                                                                   H  H  Br Q23                                           44                                                                               H     (CH.sub.2).sub.5 Q82                                                                           H  H  Br Q23                                           45                                                                               H     (CH.sub.2).sub.5 Q83                                                                           H  H  Br Q23                                           46                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                   H  H  Br Q23                                           47                                                                               H     (CH.sub.2).sub.5 CON-n-Pr.sub.2                                                                H  H  Br Q23                                           48                                                                               H     (CH.sub.2).sub.5 COQ87                                                                         H  H  Br Q23                                           49                                                                               H     (CH.sub.2).sub.5 CO.sub.2 H                                                                    H  H  Cl Q16                                           50                                                                               H     (CH.sub.2).sub.3 COQ83                                                                         H  H  Cl Q23                                           51                                                                               H     (CH.sub.2).sub.7 COQ83                                                                         H  H  Cl Q76                                           52                                                                               H     (CH.sub.2).sub.7 COQ83                                                                         H  H  Cl Q76.HCl                                       53                                                                               H     (CH.sub.2).sub.5 CONMe.sub.2                                                                   H  H  Cl Q16                                           54                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                   H  H  Cl Q16                                           55                                                                               H     (CH.sub.2).sub.5 CON-n-Pr.sub.2                                                                H  H  Cl Q16                                           56                                                                               H     (CH.sub.2).sub.5 COQ82                                                                         H  H  Cl Q16                                           57                                                                               H     (CH.sub.2).sub.5 COQ83                                                                         H  H  Cl Q16                                           58                                                                               H     (CH.sub.2).sub.5 COQ87                                                                         H  H  Cl Q16                                           59                                                                               H     (CH.sub.2).sub.7 CO.sub.2 Me                                                                   H  H  Br Q23                                           60                                                                               H     (CH.sub.2).sub.3 COQ84                                                                         H  H  Cl Q23                                           61                                                                               H     (CH.sub.2).sub.5 COQ84                                                                         H  H  Cl Q23                                           62                                                                               H     (CH.sub.2).sub.7 COQ84                                                                         H  H  Cl Q23                                           63                                                                               H     (CH.sub.2).sub.7 CONMe.sub.2                                                                   H  H  Br Q23                                           64                                                                               H     (CH.sub.2).sub.7 CONEt.sub.2                                                                   H  H  Br Q23                                           65                                                                               H     (CH.sub.2).sub.7 CON-n-Pr.sub.2                                                                H  H  Br Q23                                           66                                                                               H     (CH.sub.2).sub.7 COQ82                                                                         H  H  Br Q23                                           67                                                                               H     (CH.sub.2).sub.7 COQ83                                                                         H  H  Br Q23                                           68                                                                               H     (CH.sub.2).sub.7 COQ87                                                                         H  H  Br Q23                                           69                                                                               H     (CH.sub.2).sub.4 COQ83                                                                         H  H  Cl Q76                                           70                                                                               H     (CH.sub.2).sub.4 COQ83                                                                         H  H  Br Q76                                           71                                                                               H     (CH.sub.2).sub.4 COQ83                                                                         H  H  Cl Q23                                           72                                                                               H     (CH.sub.2).sub.5 COQ83                                                                         H  H  Cl Q76.HCl                                       73                                                                               H     (CH.sub.2).sub.5 COQ83                                                                         H  H  Cl Q76.Q105                                      74                                                                               H     (CH.sub.2).sub.5 COQ85                                                                         H  H  Cl Q76                                           75                                                                               H     (CH.sub.2).sub.5 COQ85                                                                         H  H  Cl Q76.HCl                                       76                                                                               H     (CH.sub.2).sub.5 COQ85                                                                         H  H  Cl Q76.Q105                                      77                                                                               H     (CH.sub.2).sub.3 COQ85                                                                         H  H  Cl Q76                                           78                                                                               H     (CH.sub.2).sub.3 COQ83                                                                         H  H  Cl Q76.HCl                                       79                                                                               H     (CH.sub.2).sub.3 COQ85                                                                         H  H  Cl Q76.HCl                                       80                                                                               H     (CH.sub.2).sub.2 Ph                                                                            H  H  Br Q76.HCl                                       81                                                                               H     (CH.sub.2).sub.4 COQ83                                                                         H  H  Cl Q76.HCl                                       82                                                                               H     (CH.sub.2).sub.4 COQ83                                                                         H  H  Br Q76.HCl                                       83                                                                               H     (CH.sub.2).sub.2 Ph                                                                            H  H  Br Q23                                           84                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Br Q23                                           85                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Br Q76.HCl                                       86                                                                               H     (CH.sub.2).sub.5 COQ95                                                                         H  H  Cl Q23                                           87                                                                               H     (CH.sub.2).sub.7 COQ95                                                                         H  H  Cl Q23                                           88                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Br Q58                                           89                                                                               H     (CH.sub.2).sub.5 CO.sub.2 H                                                                    H  H  Br Q76                                           90                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Cl Q23                                           91                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Cl Q76                                           92                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Cl Q76.HCl                                       93                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Cl Q76.Q105                                      94                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Br Q61                                           95                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                 H  H  Cl Q76                                           96                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                 H  H  Br Q23                                           97                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                 H  H  Br Q76                                           98                                                                               H     (CH.sub.2).sub.6 NHSO.sub.2 Ph                                                                 H  H  Br Q23                                           99                                                                               H     (CH.sub.2).sub.6 NHSO.sub.2 Ph                                                                 H  H  Br Q76                                          100                                                                               H     (CH.sub.2).sub.4 NHSO.sub.2 Ph                                                                 H  H  Cl Q23                                          101                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Br Q76                                          102                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q76                                          103                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q23                                          104                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q76                                          105                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Cl Q76                                          106                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q76                                          107                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  CN Q76                                          108                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  Br Q76                                          109                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  Br Q23                                          110                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  Br Q28                                          111                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  Br Q76                                          112                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  Br Q23                                          113                                                                               H     (CH.sub.2).sub.5 CONHPh                                                                        H  H  Br Q76.HCl                                      114                                                                               H     (CH.sub.2).sub.3 CONHPh                                                                        H  H  Br Q76                                          115                                                                               H     (CH.sub.2).sub.3 CONHQ96                                                                       H  H  Br Q23                                          116                                                                               H     (CH.sub.2).sub.3 CONHQ97                                                                       H  H  Br Q23                                          117                                                                               H     (CH.sub.2).sub.5 CONHQ97                                                                       H  H  Br Q23                                          118                                                                               H     (CH.sub.2).sub.3 CONEt.sub.2                                                                   H  H  Br Q76                                          119                                                                               H     (CH.sub.2).sub.5 CON(Me)Q1                                                                     H  H  Br Q76                                          120                                                                               H     (CH.sub.2).sub.3 CON(Me)Q1                                                                     H  H  Br Q23                                          121                                                                               H     (CH.sub.2).sub.5 CON(Me)Ph                                                                     H  H  Br Q76.HCl                                      122                                                                               H     (CH.sub.2).sub.3 CON(Me)Ph                                                                     H  H  Br Q76                                          123                                                                               H     (CH.sub.2).sub.5 CON(Et)Ph                                                                     H  H  Br Q76.HCl                                      124                                                                               H     (CH.sub.2).sub.3 CON(Et)Ph                                                                     H  H  Br Q76                                          125                                                                               H     (CH.sub.2).sub.5 CON(Et)Ph                                                                     H  H  Br Q23                                          126                                                                               H     (CH.sub.2).sub.5 COQ87                                                                         H  H  Br Q76.HCl                                      127                                                                               H     (CH.sub.2).sub.3 COQ87                                                                         H  H  Br Q76                                          128                                                                               H     (CH.sub.2).sub.5 COQ86                                                                         H  H  Cl Q23                                          129                                                                               H     (CH.sub.2).sub.4 NHCOPh                                                                        H  H  Br Q76                                          130                                                                               H     (CH.sub.2).sub.4 NHCOPh                                                                        H  H  Br Q23                                          131                                                                               H     (CH.sub.2).sub.6 Q88                                                                           H  H  Br Q76                                          132                                                                               H     (CH.sub.2).sub.5 Q88                                                                           H  H  Br Q76                                          133                                                                               H     (CH.sub.2).sub.6 Q88                                                                           H  H  Br Q23                                          134                                                                               H     (CH.sub.2).sub.6 Q90                                                                           H  H  Br Q76                                          135                                                                               H     (CH.sub.2).sub.5 Q90                                                                           H  H  Br Q76.HCl                                      136                                                                               H     (CH.sub.2).sub.5 NHSO.sub.2 Me                                                                 H  H  Br Q76                                          137                                                                               H     (CH.sub.2).sub.5 Q90                                                                           H  H  Br Q23                                          138                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 Me                                                                 H  H  Br Q76                                          139                                                                               H     (CH.sub.2).sub.5 NHSO.sub.2 Me                                                                 H  H  Br Q23                                          140                                                                               H     (CH.sub.2).sub.3 NHSO.sub.2 Me                                                                 H  H  Br Q23                                          141                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                              H  H  Br Q76                                          142                                                                               H     (CH.sub.2).sub.4 N(Me)SO.sub.2 Ph                                                              H  H  Br Q76                                          143                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                              H  H  Br Q23                                          144                                                                               H     (CH.sub.2).sub.4 N(Me)SO.sub.2 Ph                                                              H  H  Br Q23                                          145                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Me                                                              H  H  Br Q76                                          146                                                                               H     (CH.sub.2).sub.5 N(Me)SO.sub.2 Me                                                              H  H  Br Q76                                          147                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Me                                                              H  H  Br Q23                                          148                                                                               H     (CH.sub.2).sub.5 N(Me)SO.sub.2 Me                                                              H  H  Br Q23                                          149                                                                               H     (CH.sub.2).sub.4 NHCO.sub.2 Me                                                                 H  H  Br Q76                                          150                                                                               H     (CH.sub.2).sub.5 NHCO.sub.2 Me                                                                 H  H  Br Q76                                          151                                                                               H     (CH.sub.2).sub.3 NHCO.sub.2 Me                                                                 H  H  Br Q76                                          152                                                                               H     (CH.sub.2 ).sub.4 NHCO.sub.2 Me                                                                H  H  Br Q23                                          153                                                                               H     (CH.sub.2).sub.5 NHCO.sub.2 Me                                                                 H  H  Br Q23                                          154                                                                               H     (CH.sub.2).sub.4 N(Me)CO.sub.2 Me                                                              H  H  Br Q76                                          155                                                                               H     (CH.sub.2).sub.5 N(Me)CO.sub.2 Me                                                              H  H  Br Q76                                          156                                                                               H     (CH.sub.2).sub.3 N(Me)CO.sub.2 Me                                                              H  H  Br Q76                                          157                                                                               H     (CH.sub.2).sub.4 N(Me)CO.sub.2 Me                                                              H  H  Br Q23                                          158                                                                               H     (CH.sub.2).sub.5 N(Me)CO.sub.2 Me                                                              H  H  Br Q23                                          159                                                                               H     (CH.sub.2).sub.5 Q89                                                                           H  H  Br Q76                                          160                                                                               H     (CH.sub.2).sub.6 Q89                                                                           H  H  Br Q76                                          161                                                                               H     (CH.sub.2).sub.4 Q89                                                                           H  H  Br Q76                                          162                                                                               H     (CH.sub.2).sub.6 Q89                                                                           H  H  Br Q23                                          163                                                                               H     (CH.sub.2).sub.4 Q89                                                                           H  H  Br Q23                                          164                                                                               H     (CH.sub.2).sub.4 OCONHPh                                                                       H  H  Br Q76.HCl                                      165                                                                               H     (CH.sub.2).sub.6 OCONHPh                                                                       H  H  Br Q76.HCl                                      166                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q76.HCl                                      167                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Cl Q76.HCl                                      168                                                                               H     (CH.sub.2).sub.4  Q2                                                                           H  H  Cl Q76                                          169                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q76.Q104                                     170                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q76.Q107                                     171                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q76.Q106                                     172                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q76.Q108                                     173                                                                               H     (CH.sub.2).sub.3 Q7                                                                            H  H  Br Q76                                          174                                                                               H     (CH.sub.2).sub.4 Q7                                                                            H  H  Br Q76                                          175                                                                               H     (CH.sub.2).sub.5 Q7                                                                            H  H  Br Q76                                          176                                                                               H     (CH.sub.2).sub.5 Q7                                                                            H  H  Cl Q76                                          177                                                                               H     (CH.sub.2).sub.3 Q7                                                                            H  H  Br Q23                                          178                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Br Q23                                          179                                                                               H     (CH.sub.2).sub.3 Q12                                                                           H  H  Br Q76                                          180                                                                               H     (CH.sub.2).sub.3 Q8                                                                            H  H  Br Q76                                          181                                                                               H     (CH.sub.2).sub.2 C(Me.sub.2)Q2                                                                 H  H  Br Q76.HCl                                      182                                                                               H     (CH.sub.2).sub.3 Q23                                                                           H  H  Br Q76                                          183                                                                               H     (CH.sub.2).sub.3 Q23                                                                           H  H  Br Q23                                          184                                                                               H     (CH.sub.2).sub.3 Q25                                                                           H  H  Br Q76                                          185                                                                               H     (CH.sub.2).sub.3 Q25                                                                           H  H  Br Q23                                          186                                                                               H     (CH.sub.2).sub.3 Q26                                                                           H  H  Br Q76                                          187                                                                               H     (CH.sub.2).sub.3 Q26                                                                           H  H  Br Q23                                          188                                                                               H     (CH.sub.2).sub.3 Q15                                                                           H  H  Br Q76                                          189                                                                               H     (CH.sub.2).sub.3 Q15                                                                           H  H  Br Q23                                          190                                                                               H     (CH.sub.2).sub.3 Q13                                                                           H  H  Br Q76                                          191                                                                               H     (CH.sub.2).sub.3 Q14                                                                           H  H  Br Q76                                          192                                                                               H     (CH.sub.2).sub.3 Q75                                                                           H  H  Br Q23                                          193                                                                               H     (CH.sub.2).sub.3 Q98                                                                           H  H  Br Q76.HCl                                      194                                                                               H     (CH.sub.2).sub.3 Q99                                                                           H  H  Br Q76                                          195                                                                               H     (CH.sub.2).sub.3 Q99                                                                           H  H  Br Q23                                          196                                                                               H     (CH.sub.2).sub.3 Q76                                                                           H  H  Br Q76                                          197                                                                               H     (CH.sub.2).sub.3 Q76                                                                           H  H  Br Q23                                          198                                                                               H     (CH.sub.2).sub.2 OPh                                                                           H  H  Br Q76                                          199                                                                               H     (CH.sub.2).sub.2 OPh                                                                           H  H  Br Q23                                          200                                                                               H     (CH.sub.2).sub.6 CN                                                                            H  H  Br Q76                                          201                                                                               H     (CH.sub.2).sub.6 CN                                                                            H  H  Br Q23                                          202                                                                               H     (CH.sub.2).sub.2 Q82.HCl                                                                       H  H  Br Q23                                          203                                                                               H     (CH.sub.2).sub.3 NMe.sub.2.HCl                                                                 H  H  Br Q23                                          204                                                                               H     (CH.sub.2).sub.2 NEt.sub.2.HCl                                                                 H  H  Br Q23                                          205                                                                               H     (CH.sub.2).sub.3 Q92.2HCl                                                                      H  H  Br Q23                                          206                                                                               H     (CH.sub.2).sub.3 Q93.2HCl                                                                      H  H  Br Q23                                          207                                                                               H     (CH.sub.2).sub.3 Q94.2HCl                                                                      H  H  Br Q23                                          208                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  Cl  Q101                                        209                                                                               H     (CH.sub.2).sub.5 CONEt.sub.2                                                                   H  H  Cl  Q101                                        210                                                                               H     C(Me)H(CH.sub.2).sub.2 Ph                                                                      H  H  Br Q76.HCl                                      211                                                                               H     (CH.sub.2).sub.3 Ph                                                                            Me H  Cl  Q101                                        212                                                                               H     (CH.sub.2).sub.2 C(Me.sub.2)Q2                                                                 H  H  Br  Q101                                        213                                                                               H     (CH.sub.2).sub.3 Q93.2HCl                                                                      H  H  Br  Q101                                        214                                                                               H     CH.sub.2 C(Me).sub.2 CH.sub.2 Q2                                                               H  H  Cl Q76                                          215                                                                               H     C(Me)H(CH.sub.2).sub.2 Ph                                                                      H  H  Br  Q101                                        216                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Cl  Q101                                        217                                                                               Et    (CH.sub.2).sub.3 Ph                                                                            H  H  Cl  Q101                                        218                                                                               i-Pr  (CH.sub.2).sub.3 Ph                                                                            H  H  Cl  Q101                                        219                                                                               H     (CH.sub.2).sub.5 NHCO.sub.2 Me                                                                 H  H  Br  Q101                                        220                                                                               H     C(Me)H(CH.sub.2).sub.2 Q2                                                                      H  H  Br Q76                                          221                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q78                                          222                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q22                                          223                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br  Q100                                        224                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br  Q102                                        225                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Ph                                           226                                                                               Me    (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q23                                          227                                                                               CH.sub.2 CO.sub.2 H                                                                  (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q23                                          228                                                                               H     (CH.sub.2).sub.3Ph                                                                             H  H  Br Q28                                          229                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q76                                          230                                                                               H     (CH.sub.2).sub.3Ph                                                                             H  H  Br Q77                                          231                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q24                                          232                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q27                                          233                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q28                                          234                                                                               H     (CH.sub. 2).sub.4 Ph                                                                           H  H  Br Q23                                          235                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Br Q76                                          236                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br  Q103                                        237                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q79                                          238                                                                               CH.sub.2 CO.sub.2 Et                                                                 (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q23                                          239                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q23                                          240                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q46                                          241                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q76                                          242                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q21                                          243                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q23                                          244                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q24                                          245                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q28                                          246                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q30                                          247                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q48                                          248                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q49                                          249                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q68                                          250                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q69                                          251                                                                               H     (CH.sub.2).sub. 3 Ph                                                                           H  H  CN Q70                                          252                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q71                                          253                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q72                                          254                                                                               H     (CH.sub.2).sub.3 Ph                                                                            H  H  CN Q73                                          255                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q76                                          256                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  CN Q76                                          257                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q21                                          258                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q23                                          259                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q28                                          260                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q16                                          261                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q17                                          262                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q35                                          263                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q36                                          264                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q71                                          265                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q41                                          266                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q43                                          267                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q44                                          268                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Br Q45                                          269                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q49                                          270                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q50                                          271                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q51                                          272                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q52                                          273                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q56                                          274                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q58                                          275                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q62                                          276                                                                               H     (CH.sub.2).sub.4 Ph                                                                            H  H  Cl Q63                                          277                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Cl Q76                                          278                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  CN Q76                                          279                                                                               Et    (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q76                                          280                                                                               Allyl (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q76                                          281                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q23                                          282                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q29                                          283                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q32                                          284                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q41                                          285                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q45                                          286                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q43                                          287                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q37                                          288                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q38                                          289                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q40                                          290                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q34                                          291                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q33                                          292                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q58                                          293                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q59                                          294                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q55                                          295                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q56                                          296                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q61                                          297                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q60                                          298                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q64                                          299                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q57                                          300                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q63                                          301                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q51                                          302                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q52                                          303                                                                               H     (CH.sub.2).sub.3  Q10                                                                          H  H  Br Q53                                          304                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q66                                          305                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q69                                          306                                                                               H     (CH.sub.2).sub.3 Q10                                                                           H  H  Br Q74                                          307                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q76                                          308                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  Me Cl Q76                                          309                                                                               H     (CH.sub.2).sub.3 Q11                                                                           Me H  Br Q76                                          310                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  CN Q76                                          311                                                                               H     (CH.sub.2).sub.4 Q11                                                                           H  H  Cl Q76                                          312                                                                               H     (CH.sub.2).sub.5 Q11                                                                           H  H  Cl Q76                                          313                                                                               H     (CH.sub.2).sub.8 Q11                                                                           H  H  Cl Q76                                          314                                                                               H     C(Me)H(CH.sub.2).sub.2 Q11                                                                     H  H  Cl Q76                                          315                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q23                                          316                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q27                                          317                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q28                                          318                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q31                                          319                                                                               H     (CH.sub.2).sub.5 Q11                                                                           H  H  Cl Q23                                          320                                                                               H     (CH.sub. 2).sub.3 Q11                                                                          H  H  Cl Q19                                          321                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q45                                          322                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q43                                          323                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q38                                          324                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q39                                          325                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q42                                          326                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q48                                          327                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q62                                          328                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q54                                          329                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q58                                          330                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q59                                          331                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q61                                          332                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q50                                          333                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q51                                          334                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q52                                          335                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q65                                          336                                                                               H     (CH.sub.2).sub.3 Q11                                                                           H  H  Cl Q67                                          337                                                                               H     (CH.sub.2).sub.3 Q3                                                                            H  H  Cl Q76                                          338                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Cl Q23                                          339                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Cl Q28                                          340                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  Cl Q76                                          341                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  CN Q76                                          342                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  Cl Q76                                          343                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  CN Q76                                          344                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  CN Q28                                          345                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  Cl Q17                                          346                                                                               H     (CH.sub.2).sub.3 Q88                                                                           H  H  Cl Q18                                          347                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  Cl Q23                                          348                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  Cl Q16                                          349                                                                               H     (CH.sub.2).sub.3 Q90                                                                           H  H  Cl Q28                                          350                                                                               H     (CH.sub.2).sub.3 Q91                                                                           H  H  Br Q76                                          351                                                                               H     (CH.sub.2).sub.3 Q91                                                                           H  H  Br Q23                                          352                                                                               H     (CH.sub.2).sub.3 Q91                                                                           H  H  Br Q19                                          353                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub. 2 Ph                                                             H  H  Cl Q76                                          354                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q2                                                              H  H  Cl Q76                                          355                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q4                                                              H  H  Cl Q76                                          356                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q2                                                              H  H  Br Q76                                          357                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q2                                                              H  H  CN Q76                                          358                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                              H  H  Cl Q23                                          359                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q2                                                              H  H  Cl Q23                                          360                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q6                                                              H  H  Cl Q23                                          361                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                              H  H  Cl Q24                                          362                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q2                                                              H  H  Cl Q28                                          363                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                              H  H  Cl Q58                                          364                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Ph                                                              H  H  Cl Q61                                          365                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Ph                                                              H  H  Br Q76                                          366                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Q2                                                              H  H  Br Q76                                          367                                                                               H     (CH.sub.2).sub.3 N(Me)SO.sub.2 Q5                                                              H  H  Br Q76                                          368                                                                               H     (CH.sub. 2).sub.2 N(Me)SO.sub.2 Q2                                                             H  H  CN Q23                                          369                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q2                                                              H  H  CN Q28                                          370                                                                               H     (CH.sub.2).sub.2 N(Me)SO.sub.2 Q3                                                              H  H  CN Q23                                          371                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q80                                          372                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q81                                          373                                                                               H     C(Me.sub.2)(CH.sub.2) Q2                                                                       H  H  Br Q76                                          374                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q2                                                                H  H  Br Q76                                          375                                                                               H     C(Et.sub.2)(CH.sub.2).sub.2 Q2                                                                 H  H  Br Q76                                          376                                                                               H     C(n-Pr.sub.2)(CH.sub.2).sub.2 Q2                                                               H  H  Br Q76                                          377                                                                               H     C(Me.sub.2)CH.sub.2 C(Me.sub.2)-Q2                                                             H  H  Br Q76                                          378                                                                               H     CH.sub.2 C(Et.sub.2)CH.sub.2 Q2                                                                H  H  Br Q76                                          379                                                                               H     CH.sub.2 C(n-Pr.sub.2)CH.sub.2 Q2                                                              H  H  Br Q76                                          380                                                                               H     (CH.sub.2).sub.2 C(Et.sub.2)Q2                                                                 H  H  Br Q76                                          381                                                                               H     (CH.sub.2).sub.2 C(n-Pr.sub.2)Q2                                                               H  H  Br Q76                                          382                                                                               H     C(Me.sub.2)(CH.sub.2).sub.3 Q2                                                                 H  H  Br Q76                                          383                                                                               H     CH.sub.2 C(Me.sub.2)(CH.sub.2).sub.2 Q2                                                        H  H  Br Q76                                          384                                                                               H     (CH.sub.2).sub.2 C(Me.sub.2)CH.sub.2 Q2                                                        H  H  Br Q76                                          385                                                                               H     (CH.sub.2).sub.3 C(Me.sub.2)Q2                                                                 H  H  Br Q76                                          386                                                                               H     C(Me.sub.2)(CH.sub.2).sub.2 C(Me.sub.2)Q2                                                      H  H  Br Q76                                          387                                                                               H     C(Me.sub.2)CH.sub.2 C(Me.sub.2)CH.sub.2 Q2                                                     H  H  Br Q76                                          388                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 C(Me.sub.2)Q2                                                     H  H  Br Q76                                          389                                                                               H     C(i-Pr.sub.2)(CH.sub.2).sub.2 Q2                                                               H  H  Br Q76                                          390                                                                               H     CH.sub.2 C(i-Pr.sub.2)CH.sub.2 Q2                                                              H  H  Br Q76                                          391                                                                               H     (CH.sub.2).sub.2 C(i-Pr.sub.2)Q2                                                               H  H  Br Q76                                          392                                                                               H     (CH.sub.2).sub.3 Q2                                                                            H  H  Br Q47                                          393                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Ph                                                                H  H  Br Q76                                          394                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CO.sub.2 H                                                        H  H  Br Q76                                          395                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CO.sub.2 Me                                                       H  H  Br Q76                                          396                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CN                                                                H  H  Br Q76                                          397                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 OH                                                                H  H  Br Q76                                          398                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 OMe                                                               H  H  Br Q76                                          399                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q98                                                               H  H  Br Q76                                          400                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q76                                                               H  H  Br Q76                                          401                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 CONEt.sub.2                                                       H  H  Br Q76                                          402                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 COQ83                                                             H  H  Br Q76                                          403                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 COQ87                                                             H  H  Br Q76                                          404                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHSO.sub.2 Ph                                                     H  H  Br Q76                                          405                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHSO.sub.2 Me                                                     H  H  Br Q76                                          406                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 N(Me)SO.sub.2 Ph                                                  H  H  Br Q76                                          407                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 N(Me)SO.sub.2 Me                                                  H  H  Br Q76                                          408                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q7                                                                H  H  Br Q76                                          409                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q6                                                                H  H  Br Q76                                          410                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q10                                                               H  H  Br Q76                                          411                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q11                                                               H  H  Br Q76                                          412                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q8                                                                H  H  Br Q76                                          413                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q9                                                                H  H  Br Q76                                          414                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHCOPh                                                            H  H  Br Q76                                          415                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q90                                                               H  H  Br Q76                                          416                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NHCO.sub.2 Me                                                     H  H  Br Q76                                          417                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 N(Me)CO.sub.2 Me                                                  H  H  Br Q76                                          418                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q89                                                               H  H  Br Q76                                          419                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 NEt.sub.2                                                         H  H  Br Q76                                          420                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q83                                                               H  H  Br Q76                                          421                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q92                                                               H  H  Br Q76                                          422                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 Q94                                                               H  H  Br Q76                                          423                                                                               H     CH.sub.2 C(Me.sub.2)CH.sub.2 OCONHPh                                                           H  H  Br Q76                                          __________________________________________________________________________

A method for preparing the compounds of the present invention is explained hereinafter.

The 3(2H)-pyridazinone derivatives of the general formula [I] and pharmaceutically acceptable salts thereof of the present invention can be prepared by the following methods as illustrated by the reaction formulas (1)-(9). ##STR29## (wherein X¹ is a chlorine atom or a bromine atom, X² is a chlorine atom, a bromine atom or a hydrogen atom, and R¹, R², R³, R⁴ and Ar are as defined above.)

In the preparation method according to the reaction formula (1), a 4,5-dihalo- or 5-halo-3(2H)-pyridazinone compound of the formula [IIA] is reacted with an arylmethylamine derivative of the formula [III] or its salt optionally in the presence of a dehydrohalogenating agent in an inert solvent to produce a compound of the formula [IA] wherein the 4-position of the compounds of the present invention of the formula [I] is bonded with X².

In the above reaction formula (1), when X² in the formula [IIA] is a chlorine atom or a bromine atom, a position isomer of the compound of the formula [IA], i.e. a compound of the formula [VA], ##STR30## (wherein R¹, R², R³, R⁴, X¹ and Ar are as defined above) having an arylmethylamino group substituted at the 4-position, is formed as a by-product, but the production ratios of the compounds of the formulas [IA] and [VA] depend primarily upon the polarity of the solvent used.

Namely, when a solvent of high polarity is used, the production ratio of the compound [IA] of the present invention tends to be high. Conversely, when a solvent of low polarity (such as benzene, toluene or hexane) is used, the production ratio of the compound [VA] tends to be high.

Therefore, as a solvent suitable for suppressing by-production of the compound of the formula [VA] and for efficient production of the compounds [IA] of the present invention, an ether type solvent (such as tetrahydrofuran or 1,4-dioxane), an amide type solvent (such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone), acetonitrile, dimethylsulfoxide, an alcohol type solvent (such as methanol, ethanol or propanol), an organic amine solvent (such as pyridine, triethylamine, N,N-dimethylaminoethanol or triethanolamine), or water, or a solvent mixture thereof, may be mentioned.

The desired compound of the formula [IA] of the present invention can readily be separated and purified from the mixture of the compounds of the formulas [IA] and [VA] by conventional methods known per se in organic synthesis, such as fractional recrystallization or various silica gel chromatography.

When a compound of the formula [IIA] wherein X² is a hydrogen atom, i.e. 5-halo-3(2H)-pyridazinone, is used, benzene, toluene, xylene, n-hexane, n-heptane and the like may also be used as a reaction solvent in addition to the above-mentioned solvents.

During the reaction between the compound of the formula [IIA] and the compound of the formula [III], hydrogen chloride or hydrogen bromide is generated. It is usually possible to improve the yield by adding to the reaction system a dehydrohalogenating agent which traps such a hydrogen halide.

Any dehydrohalogenating agent may be used so long as it does not adversely affect the reaction and is capable of trapping a hydrogen halide. As such a dehydrohalogenating agent, an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate, or an organic base such as N,N-dimethylaniline, N,N-diethylaniline, trimethylamine, triethylamine, N,N-dimethylaminoethanol or pyridine, may be mentioned.

Otherwise, the starting material arylmethylamine derivative of the formula [III] may be used in an excessive amount as the dehydrohalogenating agent. This gives an improved yield in many cases.

The reaction temperature may be within a range of from 10° C. to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials may optionally be set. However, the arylmethylamine derivative of the formula [III] or its salt may be used usually in an amount of from 1 to 10 mols, preferably from 1.2 to 5 mols, relative to one mol of the 4,5-dihalo-or 5-halo-3(2H)-pyridazinone derivative of the formula [IIA].

The 4,5-dihalo or 5-halo-3(2H)-pyridazinone derivative of the formula [IIA] can be prepared by a conventional process or by application of a conventional organic reaction as described below.

Namely, the 4,5-dihalo- or 5-halo-3(2H)-pyridazinone derivative of the formula [IIA] can be prepared by the method disclosed in the above-mentioned reference (c).

Among the arylmethylamine derivatives of the formula [III] and their salts in Process (1), those not available as commercial products can be prepared by the method disclosed in Japanese Unexamined Patent Publication No. 267560/1986. (Corresponding U.S. Pat. No. 5,098,900 and European Patent No. 0,186,817). ##STR31## (wherein R¹, R², R³, R⁴, X¹ and Ar are as defined above.)

The above reaction formula (2) illustrates a method for preparing a 4-cyano-5-arylmethylamino derivative of the formula [IB] of the present invention by halogen-substitution reaction between a 4-halo-5-arylmethylamino derivative of the formula [IB-a] and a metal cyanide of the formula [IV].

Examples of metal M include a lithium atom, a sodium atom, a potassium atom, a copper atom and the like.

As a reaction solvent, an amide type solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone etc., an alcohol solvent such as methanol, ethanol, n-propanol, n-butanol etc., dimethyl sulfoxide and their water-containing solvents are preferably used.

The reaction temperature varies depending upon the reactants used, but it is usually within a range of from room temperature to the boiling point of the solvent used for the reaction. Generally, the reaction of a bromine atom as a halogen atom at the 4-position proceeds under milder temperature conditions than the reaction of a chlorine atom.

The molar ratio of the starting materials can be optionally determined, and it is sufficient that the metal cyanide of the formula [IV] is used in an amount of from 1.2 to 10 mols relative to one mol of the 4-halo-5-arylmethylamino derivative of the formula [IB-a].

The desired compound can readily be isolated and purified by a method known in organic synthesis such as recrystallization, various silica gel chromatography or distillation. ##STR32## (wherein R^(1') is a straight chained or branched C₁ -C₄ alkyl group, a C₃ -C₄ alkenyl group or (CH₂)_(n) CO₂ R⁵, hal is a chlorine atom, a bromine atom, an iodione atom or other eliminatable functional groups, and n, R², R³, R⁴, R⁵, X and Ar are as defined above.)

The above reaction formula (3) illustrates a method for preparing in substitution product at the 2-position of the formula [I-b] of the present invention by reacting a compound of the formula [I-a] wherein the 2-position of the pyridazinone is occupied by a hydrogen atom, among the compounds of the formula [I] of the present invention, with a reactive derivative having an eliminatable group such as a halogeno derivative, an alkyl sulfonate derivative or a phenyl sulfonate derivative as expressed by the formula R^(1') -hal.

The present reaction can be generally conducted in the presence of an inorganic base such as potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, lithium hydroxide etc., or an organic base such as triethylamine, tri-n-propylamine etc.

When R³ is an alkyl group in the compound of the formula [I-a], a metal hydride and an organometallic compound such as sodium hydride, n-butyl lithium etc. may be used in addition to the above inorganic bases.

As a reaction solvent, a ketone type solvent (acetone, methyl ethyl ketone, diethyl ketone etc.), an amide type solvent (formamide, N,N-dimethylformamide, N,N-dimethylacetamide etc.), an alcohol type solvent (methanol, ethanol etc.), water and a mixture thereof can be suitably used when an inorganic base or an organic base is used, and an ether type solvent can be suitably used when a metal hydride is used.

In the case of using the inorganic base or the organic base, the reaction temperature is usually within a range of from 0° C. to the boiling point of the solvent, and in the case of using the metal hydride or the organometallic compound, it is usually within a range of from -78° C. to 60° C.

The molar ratio of the starting materials may optionally be determined. However, it is sufficient that the reactive derivative of the formula R^(1') -hal is used in an amount of from 1 to 5 mols relative to one mol of the compound of the formula [I-a].

The desired compound can be isolated and purified in accordance with the method as described with respect to the reaction formula (2). ##STR33## (wherein R¹, R², R³, R⁴, X, Ar and hal are as defined above.)

The above reaction formula (4) illustrates a method for preparing a compound of the formula [I] of the present invention by reacting a 6-hydroxy-5-arylmethylamino derivative of the formula [IC-a] with a reactive derivative of the formula R² -hal. The 6-hydroxy-5-arylmethyl derivative of the formula [IC-a] used as the starting material in the present reaction can be prepared in accordance with the methods disclosed in the above-mentioned reference (c) and reaction formula (2).

With regard to the reaction conditions, it is possible to employ reaction conditions similar to those in the above reaction formula (3). ##STR34## (wherein M¹ is an alkali metal atom, R^(1") is a protective group, and R¹, R², R³, R⁴, X and Ar are as defined above.)

The above reaction formula (5) illustrates a method for preparing a 6-alkoxy-5-arylmethylamino derivative of the formula [I] or the formula [I-a] of the present invention by substitution reaction of the nitro group of a 6-nitro-5-arylmethylamino derivative of the formula [ID-a] or the formula [ID-b] with an alkali metal alkoxide of the formula [VI]. The 6-nitro derivative of the formula [ID-a] and [ID-b] used as the starting material in the present reaction can be prepared in accordance with the method disclosed in the above-mentioned reference (c).

Among the desired compounds, a compound having hydrogen at 2-position of pyridazinone, can be prepared by the direct route as shown in the reaction formula (5)-(i) wherein R¹ of the formula [ID-a] and [I] is hydrogen, or by route as shown in the reaction formula (5)-(ii) which comprises converting the 6-nitro-5-arylmethylamino derivative of the formula [ID-b] protected at 2-position with R^(1") to a compound of the formula [ID-c] and then removing the protecting group R^(1"), to obtain the desired compound. The yield is usually better in the latter method in many cases.

As the protective group R^(1"), tetrahydropyranyl, tetrahydrofuranyl, 2-trimethylsilylethoxymethyl (Me₃ SiCH₂ CH₂ OCH₂ --), pivaloyloxymethyl(Me₃ C--CO₂ CH₂ --), benzyloxymethyl ##STR35## hydroxymethyl, methoxymethyl (MeOCH₂ --) or CO₂ R wherein R is a lower alkyl group, is preferably used.

The removal of the protective group R^(1") can easily be conducted by a conventional method for the removal of such protective groups.

Here, the alkali metal of the formula M¹ includes lithium, sodium and potassium.

Therefore, an alkali metal alkoxide of the formula [VI] used as a nucleophilic agent includes a metal alkoxide as defined by the above M¹ and R².

There is no particular restriction as to the reaction solvent so long as it is inert to the reaction, and there are enumerated an amide type solvent (such as N-methylpyrrolidone, formamide, N,N-dimethylformamide or N,N-dimethylacetamide), an ether type solvent (such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane), a benzene type solvent (such as benzene, toluene or xylene), and a mixture thereof.

The reaction temperature varies depending upon the reactants used. It is usually within a range of from -15° C. to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials can be optionally determined, and it is sufficient that the alkali metal alkoxide of the formula [VI] is used in an amount of from 1.2 to 10 mols relative to one mol of the 6-nitro-5-arylmethylamino derivative of the formula [ID-a] or the formula [ID-b].

The desired compound can readily be isolated and purified by a method known in organic syntheses such as recrystallization, various silica gel chromatography or distillation. ##STR36## (wherein R¹, R², R³, R⁴, X¹ and Ar are as defined above.)

The above reaction formula (6) illustrates a method for preparing the compound of the formula [IE] of the present invention wherein the 4-position is occupied by hydrogen by reductively removing a halogen atom of the 4-halo derivative of the formula [IB-a].

As the reduction method, catalytic hydrogenation is generally used. As a catalyst, there are enumerated palladium, platinum oxide, Raney nickel and the like, and the reaction proceeds relatively smoothly under a hydrogen pressure of from 1 to 10 atoms.

When R² contains an atom which becomes a catalyst poison, a preferable result is sometimes obtained by using a metal hydride such as tri-n-butyltin hydride or lithium aluminum hydride.

As a reaction solvent, a protonic solvent is used in the case of catalytic hydrogenating reaction, and an ether type solvent is generally used in the case of using a metal hydride.

The reaction temperature may usually be within a range of from -10° C. to 100° C., and the reaction usually proceeds smoothly. ##STR37## (wherein R¹, R³, R⁴, R⁵, R⁷, R⁸, A¹, X and Ar are as defined above.)

The above reaction formula (7) illustrates a method for preparing a 6-aminocarbonylalkyleneoxy derivative of the formula [IF-b] by subjecting a 6-ω-carboxyalkyleneoxy derivative or 6-ω-alkoxycarbonylalkyleneoxy derivative of the formula [IF-a] and an amine compound of the formula [VII] to condensation reaction including dehydration or dealcohol.

As a condensation process where R⁵ is a hydrogen atom, there can be used a condensation method known in peptide synthesis, for example, acid chloride method, mixed acid anhydride method, or a condensation method using a condensation agent such as di-cyclohexylcarbodiimide, carbonyldiimidazole or N-hydroxysuccinic acid imide, and a condensation method is selected depending on the reactivity of amines of the formula [VII]. As a reaction condition, conditions usually used may be employed.

Among amines of the formula [VII], in the reaction with a highly nucleophilic amines, the condensation reaction can proceed even by using esters wherein R⁵ is an alkyl group. In this case, the solvent is not specially limited and any solvent can be used so long as it does not adversely affect the reaction. In some cases, the reaction can proceed in the absence of a solvent. The reaction temperature is within a range from room temperature to 200° C., more usually from 50° to 150° C. ##STR38## (wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸, X, Z² and A¹ are as defined above.)

The above reaction formula (8) illustrates a method for preparing an amide derivative of the formula [IG-b] by subjecting a 5-(ω-carboxyalkyleneoxy)phenylmethylamino derivative or 5-(ω-alkoxycarbonylalkyleneoxy)phenylmethylamino derivative of the formula [IG-a] and an amine compound of the formula [VII] to condensation reaction.

The present reaction can be carried out in the same manner as in the reaction formula (7). ##STR39## (wherein R¹, R², R³, R⁴, R²⁰ and X are as defined above.)

The above reaction formula (9) illustrates a method for preparing an N-oxypyridylmethylamino derivative of the formula [IH-b] by oxidizing a nitrogen atom on the pyridine ring of a 5-pyridylmethylamino derivative of the formula [IH-a]. Examples of an oxidizing agent include performic acid, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, t-butylhydroperoxide, aqueous hydrogen peroxide and the like.

As a reaction solvent, there are enumerated a halogen type solvent (carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane etc.), an ether type solvent (diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), a benzene type solvent (benzene, toluene etc.), an alcohol type solvent (methanol, ethanol, t-butanol etc.), acetic acid, formic acid and the like. In some cases, a transition metal complex may be added as a catalyst.

The reaction temperature may be usually within a range of from -20° C. to the boiling point of the solvent used for the reaction.

The molar ratio of the starting materials may optionally be set, but the oxidizing agent may be used usually in an amount of from 1 to 10 mols, preferably from 1.2 to 5 mols, relative to one mol of the 5-pyridylmethylamino derivative of the formula [IH-a].

The desired compound can readily be isolated and purified by a method known in organic synthesis such as recrystallization, various silica gel chromatography or distillation.

As the manner of administration of the 3(2H)-pyridazinones of the formula [I] or their pharmaceutically acceptable salts of the present invention, there may be mentioned a non-oral administration by injection (subcutaneous, intravenous, intramuscular of intraperitoneal injection), an ointment, a suppository or an aerosol, or an oral administration in the form of tablets, capsules, granules, pills, syrups, liquids, emulsions or suspension.

The above pharmacological composition contains a compound of the present invention in an amount of from about 0.1 to about 99.5% by weight, preferably from about 0.5 to 95% by weight, based on the total weight of the composition.

To the compound of the present invention or to the composition containing the compound of the present invention, other pharmacologically active compounds may be incorporated.

Further, the composition of the present invention may contain a plurality of compounds of the present invention.

The clinical dose of the compound of the present invention varies depending upon the age, the body weight, the sensitivity or the sympton, etc. of the patient. However, the effective daily dose is usually from 0.003 to 1.5 g, preferably from 0.01 to 0.6 g, for an adult.

However, if necessary, an amount outside the above range may be employed.

The compounds of the present invention may be formulated into various suitable formulations depending upon the manner of administration, in accordance with conventional methods commonly employed for the preparation of pharmaceutical formulations.

Namely, tablets, capsules, granules or pills for oral administration, may be prepared by using an excipient such as sugar, lactose, glucose, starch or mannitol; a binder such as syrups, gum arabic, gelatin, sorbitol, tragacanth gum, methyl cellulose or polyvinylpyrrolidone; a disintegrant such as starch, carboxymethyl cellulose or its calcium salts, crystal cellulose powder or polyethylene glycol; a gloss agent such as talc, magnesium or calcium stearate or silica; or a lubricant such as sodium laurate or glycerol.

The injections, solutions, emulsions, suspensions, syrups or aerosols, may be prepared by using a solvent for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, or polyethylene glycol; a surfactant such as a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene ether of hydrogenated castor oil or lecithin, a suspending agent such as a sodium salt of carboxymethyl cellulose, a cellulose derivative such as methyl cellulose, or a natural rubber such as tragacanth gum or gum arabic; or a preservative such as a paraoxy benzoic acid ester, benzalkonium chloride or a salt of sorbic acid.

Likewise, the suppositories may be prepared by using e.g. polyethylene glycol, lanolin or coconut butter.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES (PREPARATION EXAMPLES, FORMULATION EXAMPLES AND TEST EXAMPLES)

Now, the present invention will be described in detail with reference to Examples (including Preparation Examples, Formulation Examples and Test Examples). However, it should be understood that the present invention is by no means restricted by these specific Examples. In Preparation Examples or in Table II, the symbols "NMR", "IR" and "MS" indicate "nuclear magnetic resonance spectrum", "infrared spectrum" and "mass spectrometry", respectively. IR was measured by the potassium bromide disk method, and NMR was measured in heavy hydrogen chloroform, unless otherwise specified.

In the MS data in Table II, only the principal peaks or typical fragment peaks are given.

PREPARATION EXAMPLE 1 4-Chloro-5-(3,4-demethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) ##STR40##

A mixture comprising 4.13 g of 4,5-dichloro-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone, 6.70 g of 3,4-dimethoxybenzylamine, 130 ml of 1,4-dioxane and 130 ml of water, was refluxed with stirring overnight. The solvent was evaporated under reduced pressure, and water was poured to the residue, whereupon the product was extracted with chloroform. The extract was washed with dilute hydrochloric acid, water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-n-hexane-diethyl ether to obtain 5.28 g of the above identified compound as colorless crystals having a melting point of from 111° C. to 112° C.

NMR δ: 11.71(1H,broad s), 6.71(3H,s), 5.02(1H,collapsed t), 4.76(2H,d), 4.11(2H,t), 3.80(6H,s), 3.57(3H,s), 2.26(2H,t), 2.1-1.2(6H,m).

MS(m/e):439(M⁺), 404, 151(100%)

PREPARATION EXAMPLE 2 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-carboxypentyloxy)-3(2H)-pyridazinone (Compound No. 2) ##STR41##

A mixture comprising 240 mg of 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) prepared in Preparation Example 1, 65 mg of sodium hydroxide, 10 ml of methanol and 1 ml of water, was stirred at 60°-70° C. for 1 hour. After the reaction liquor was evaporated under reduced pressure, water was poured to the residue, and the resultant solution was adjusted to pH 1-2 with dilute hydrochloric acid, whereupon the product was extracted with chlorform. The extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 192 mg of the above identified compound as colorless crystals having a melting point of from 150.5° C. to 151.5° C.

NMR δ: 6.70(3H,s), 5.14(1H,collapsed t), 4.75(2H,d), 4.10(2H,t), 3.79(6H,s), 2.29(2H,t), 2.0-1.2(6H,m).

IR: (ν_(max) ^(KBr) cm⁻¹): 3100, 2910, 1720, 1610.

MS(m/e): 425(M⁺), 390, 151(100%).

PREPARATION EXAMPLE 3 4-Bromo-5-(3-pyridylmethylamino)-6-(3-phenylpropoxy)-3(2H)-pyridazinone hydrochloride (Compound No. 85) ##STR42##

2.50 g of 4-bromo-5-(3-pyridylmethylamino)-6-(3-phenylpropoxy)-3(2H)-pyridazinone (Compound No. 101) was dissolved in 150 ml of a 10% hydrogen chloride methanol solution, and the resultant solution was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-diethyl ether to obtain 2.68 g of the above identified compound as colorless crystals having a melting point of from 203° C. to 205° C.

MS(m/e): 414(M⁺ -HCl), 335, 322, 296, 217, 118(100%).

PREPARATION EXAMPLE 4 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-N,N-diethylaminocarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 12) ##STR43##

60 mg of ethyl chlorocarbonate was added to a mixture comprising 200 mg of 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-carboxypentyloxy)-3(2H)-pyridazinone (Compound No. 2) prepared in Preparation Example 2, 60 mg of triethylamine and 10 ml of tetrahydrofuran under cooling with ice, and the resultant mixture was stirred at the same temperature for 1.5 hours. 100 mg of diethylamine was further added thereto, and the resultant mixture was further stirred for 2.5 hours after removing the ice bath, and the solvent was evaporated under reduced pressure. Water was poured to the residue, and the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 209 mg of the above identified compound as colorless crystals having a melting point of from 148° C. to 149.5° C.

NMR δ: 6.75(3H,s), 5.15(1H,collapsed t), 4.79(2H,d), 4.15(2H,t), 3.83(6H,s), 3.81, 3.76(each 2H,q), 2.27(2H,t), 2.1-1.9(6H,m), 1.15, 1.10(each 3H,t).

MS(m/e): 480(M⁺), 445, 310, 275, 170(100%), 151.

PREPARATION EXAMPLE 5 4-Chloro-5-(3,4-dimethoxybenzylamino)-6-(5-N-methylaminocarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 8) ##STR44##

A mixture comprising 200 mg of 4-chloro-5-(3,4-dimethoxybenzylamino)-6-(5-methoxycarbonylpentyloxy)-3(2H)-pyridazinone (Compound No. 1) prepared in Preparation Example 1, 2 ml of 40% methylamine aqueous solution and 6 ml of methanol was refluxed for 8 hours. The reaction mixture was evaporated under reduced pressure, and the product was extracted with chloroform. The extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 146 mg of the above identified compound as colorless crystals having a melting point of from 103° C. to 104° C.

NMR δ: 11.65(1H,broad s), 6.73(3H,s), 6.0-5.5(1H,broad m), 5.02(1H,collapsed t), 4.76(2H,d), 4.10(2H,t), 3.81(6H,s), 2.74(3H,d), 2.12(2H, collapsed t), 1.9-1.3(6H,m).

MS(m/e): 438(M⁺), 403, 310, 274, 151(100%), 128.

PREPARATION EXAMPLE 6 4-Chloro-5-(3-pyridylmethylamino)-6-[5-(1-piperidinocarbonylpentyloxy)]-3(2H)-pyridazinone fumarate (Compound No. 73) ##STR45##

A mixture comprising 1.0 g of 4-chloro-5-(3-pyridylmethylamino)-6-[5-(1-piperidinocarbonylpentyloxy)]-3(2H)-pyridazinone (Compound No. 33), 268 mg of fumaric acid and 20 ml of methanol was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the solid residue was crystallized from chloroform-ethylacetate to obtain 1.06 g of the above identified compound as colorless crystals having a melting point of from 156° C. to 158° C.

MS(m/e): 433[M⁺ -(CH-CO₂ H)₂ ], 398, 287, 251, 216, 182(100%).

PREPARATION EXAMPLE 7 4-Cyano-5-(3-pyridylmethylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 107) ##STR46##

A mixture comprising 1.0 g of 4-bromo-5-(3-pyridylmethylamino)-6-[3-(4-chlorophenylpropoxy)]-3-(2H)-pyridazinone (Compound No. 106), 587 mg of copper cyanide and 20 ml of N-methylpyrrolidone was stirred at 120°-130° C. for 6 hours. After cooling the resultant mixture to room temperature, a saturated ammonium chloride aqueous solution was added thereto, whereupon the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from acetonitrile to obtain 313 mg of the above identified compound as slightly yellow crystals having a melting point of from 188° C. to 190° C.

MS(m/e): 395(M⁺), 350, 243, 152(100%), 124.

IR: (ν_(max) ^(KBr) cm⁻¹): 3100, 2850, 2200, 1620.

PREPARATION EXAMPLE 8 2-Ethoxycarbonylmethyl-4-bromo-5-(3,4-dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 238) ##STR47##

A mixture comprising 100 mg of 4-bromo-5-(3,4-dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 239), 33 mg of potassium carbonate, 49 mg of ethyl bromoacetate, 316 mg of sodium iodine and 5 ml of methyl ethyl ketone, was stirred under reflux for 5 hours. After removing the undissolved material by filtration, the solvent was evaporated under reduced pressure, and water was poured to the residue, whereupon the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elute: n-hexane/ethyl acetate=1/1) to obtain 82 mg of the above identified compound as colorless oil.

MS(m/e): 593(M⁺), 514, 288, 259, 151(100%).

PREPARATION EXAMPLE 9 2-(Carboxymethyl)-4-bromo-5-(3,4-dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 227) ##STR48##

A mixture comprising 80 mg of 2-ethoxycarbonylmethyl-4-bromo-5-(3,4-dimethoxybenzylamino)-6-[3-(4-chlorophenylpropoxy)]-3(2H)-pyridazinone (Compound No. 238) prepared in Preparation Example 8, 16 mg of sodium hydroxide, 2 ml of methanol and 0.2 ml of water, was stirred at room temperature for 2 hours. After the reaction liquor was evaporated under reduced pressure, water was poured to the residue, and the resultant solution was adjusted to pH 1-2 with dilute hydrochloric acid, whereupon the product was extracted with chloroform. The extract was washed with brine, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the residue was crystallized from chloroform-diethyl ether to obtain 49 mg of the above identified compound as colorless crystals having a melting point of from 140° C. to 141° C.

MS(m/e): 486(M⁺ -Br), 427, 371, 151(100%).

PREPARATION EXAMPLE 10 4-Bromo-5-[3-(N-oxypyridylmethylamino)]-6-(3-phenylpropoxy)-3(2H)-pyridazinone (Compound No. 230) ##STR49##

A mixture comprising 250 mg of 4-bromo-5-(3-pyridylmethylamino)-6-(3-phenylpropoxy)-3(2H)-pyridazinone, 167 mg of meta-chloroperbenzoic acid, and 10 ml of dichloromethane, was stirred at room temperature for 6 hours. To the resultant mixture, were added a saturated sodium hydrogencarbonate aqueous solution and chloroform, and the organic layer was separated. The remaining aqueous layer was reextracted with chloroform, and this extract was combined with the former organic layer. The combined extract was washed with water and brine in order, and was dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting solid residue was crystallized from chloroformdiethyl ether to obtain the above identified compound as colorless crystals having a melting point of from 191° C. to 192° C.

MS(m/e): 414(M⁺ -0), 335, 323, 295, 217, 91(100%).

Compounds described in the following Table II were prepared in accordance with the above Preparation Examples. The structures of the compounds should be referred to Compound Numbers as shown in Table I. The most right column of Table II indicates Preparation Example Numbers applied.

                  TABLE II                                                         ______________________________________                                         Com-                                 Exam-                                     pound Melting                        ple                                       No.   point (°C.)                                                                        MS (m/e)            No.                                       ______________________________________                                          1    111˜112                                                                             see Example 1       1                                          2    150.5˜151.5                                                                         see Example 2       1                                          3    111.5˜112.5                                                                         380(M.sup.+), 345(100%)                                                                            1                                          4      195˜195.5                                                                         366(M.sup.+), 92(100%)                                                                             2                                          5    171˜172                                                                             338(M.sup.+), 92(100%)                                                                             1                                          6      240˜240.5                                                                         292(M.sup.+ --H.sub.2 O), 92(100%)                                                                 2                                          7    194˜198                                                                             324(M.sup.+ --HCl), 92(100%)                                                                       3                                          8    103˜104                                                                             see Example 5       5                                          9    179˜180                                                                             452(M.sup.+), 151(100%)                                                                            4                                          10     167˜167.5                                                                         424(M.sup.+), 151(100%)                                                                            4                                          11   164˜165                                                                             494(M.sup.+), 184(100%)                                                                            4                                          12     148˜149.5                                                                         see Example 4       4                                          13   155˜156                                                                             520(M.sup.+), 210(100%)                                                                            4                                          14   135.5˜136.5                                                                         425(M.sup.+), 151(100%)                                                                            1                                          15     167˜168.5                                                                         397(M.sup.+), 151(100%)                                                                            2                                          16   163˜164                                                                             424(M.sup.+), 151(100%)                                                                            4                                          17   136˜138                                                                             452(M.sup. +), 151(100%)                                                                           4                                          18     181˜181.5                                                                         466(M.sup.+), 155(100%)                                                                            4                                          19   167˜168                                                                             397(M.sup.+), 151(100%)                                                                            1                                          20   192˜194                                                                             369(M.sup.+), 151(100%)                                                                            2                                          21   182˜185                                                                             542(M.sup.+), 151(100%)                                                                            1                                          22   163˜165                                                                             483(M.sup.+), 92(100%)                                                                             1                                          23   200˜201                                                                             494(M.sup.+), 151(100%)                                                                            1                                          24   Solid      435(M.sup.+), 217(100%)                                                                            1                                          25     108˜108.5                                                                         508(M.sup.+), 198(100%)                                                                            4                                          26   189˜190                                                                             492(M.sup.+), 182(100%)                                                                            4                                          27     201˜201.5                                                                         478(M.sup.+), 168(100%)                                                                            4                                          28   163˜164                                                                             421(M.sup.+), 170(100%)                                                                            4                                          29   173˜175                                                                             393(M.sup.+), 142(100%)                                                                            4                                          30   108.5˜109                                                                           467(M.sup.+), 151(100%)                                                                            1                                          31   132.5˜133                                                                           418(M.sup.+ --Cl), 151(100%)                                                                       1                                          32   165˜166                                                                             419(M.sup.+), 168(100%)                                                                            4                                          33   173.5˜176                                                                           433(M.sup.+), 182(100%)                                                                            4                                          34   169.5˜170                                                                           480(M.sup.+), 170(100%)                                                                            4                                          35     145˜146.5                                                                         508(M.sup.+), 198(100%)                                                                            4                                          36   127˜128                                                                             536(M.sup.+), 226(100%)                                                                            4                                          37   162˜163                                                                             506(M.sup.+), 151(100%)                                                                            4                                          38   163.5˜164                                                                           520(M.sup.+), 151(100%)                                                                            4                                          39   157.5˜158                                                                           522(M.sup.+), 151(100%)                                                                            4                                          40     145˜145.5                                                                         423(M.sup.+), 135(100%)                                                                            1                                          41   125˜126                                                                             483(M.sup.+), 151(100%)                                                                            1                                          42   166˜167                                                                             469(M.sup.+), 151(100%)                                                                            2                                          43     144˜144.5                                                                         496(M.sup.+), 151(100%)                                                                            4                                          44     180˜180.5                                                                         522(M.sup.+), 151(100%)                                                                            4                                          45     161˜161.5                                                                         536(M.sup.+), 151(100%)                                                                            4                                          46   114˜116                                                                             524(M.sup.+), 170(100%)                                                                            4                                          47   136˜137                                                                             552(M.sup.+), 198(100%)                                                                            4                                          48   135˜136                                                                             538(M.sup.+), 151(100%)                                                                            4                                          49   157˜158                                                                             409(M.sup.+), 135(100%)                                                                            2                                          50   153˜155                                                                             464(M.sup.+), 151(100%)                                                                            4                                          51   114˜116                                                                             461(M.sup.+), 217(100%)                                                                            4                                          52   Hygroscopic                                                                               461(M.sup.+ --HCl), 217(100%)                                                                      3                                               solid                                                                     53   103˜104                                                                             436(M.sup.+), 135(100%)                                                                            4                                          54   123˜ 124                                                                            464(M.sup.+), 170(100%)                                                                            4                                          55   124˜125                                                                             492(M.sup.+), 198(100%)                                                                            4                                          56   148˜149                                                                             462(M.sup.+), 168(100%)                                                                            4                                          57   144˜145                                                                             476(M.sup.+), 182(100%)                                                                            4                                          58   121˜122                                                                             478(M.sup.+), 135(100%)                                                                            4                                          59   121˜122                                                                             432(M.sup.+ --Br), 151(100%)                                                                       1                                          60   118˜119                                                                             478(M.sup.+), 151(100%)                                                                            4                                          61     187˜187.5                                                                         506(M.sup.+), 196(100%)                                                                            4                                          62   165.5˜166                                                                           534(M.sup.+), 98(100%)                                                                             4                                          63   156.5˜157                                                                           524(M.sup.+), 170(100%)                                                                            4                                          64     133˜133.5                                                                         552(M.sup.+), 198(100%)                                                                            4                                          65     116˜116.5                                                                         580(M.sup.+), 226(100%)                                                                            4                                          66   148.5˜150                                                                           550(M.sup.+), 196(100%)                                                                            4                                          67   150˜151                                                                             564(M.sup.+), 210(100%)                                                                            4                                          68   141˜142                                                                             566(M.sup.+), 487(100%)                                                                            4                                          69   87˜89                                                                               419(M.sup.+), 84(100%)                                                                             4                                          70   Solid      463(M.sup.+), 84(100%)                                                                             4                                          71   112˜114                                                                             478(M.sup.+), 168(100%)                                                                            4                                          72   170˜173                                                                             433(M.sup.+ --HCl), 182(100%)                                                                      3                                          73   156˜158                                                                             see Example 6       6                                          74   160˜162                                                                             461(M.sup.+), 210(100%)                                                                            4                                          75   Hygroscopic                                                                               461(M.sup.+ --HCl), 210(100%)                                                                      3                                               solid                                                                     76   135˜137                                                                             461[M.sup.+ --(CH--CO.sub.2 H).sub.2 ],                                                            6                                                          210(100%)                                                      77   142˜144                                                                             433(M.sup.+), 182(100%)                                                                            4                                          78   Hygroscopic                                                                               405(M.sup.+ --HCl), 153(100%)                                                                      3                                               solid                                                                     79   Hygroscopic                                                                               433(M.sup.+ --HCl), 182(100%)                                                                      3                                               solid                                                                     80   178˜181                                                                             400(M.sup.+ --HCl), 105(100%)                                                                      3                                          81   Hygroscopic                                                                               419(M.sup.+ --HCl), 168(100%)                                                                      3                                               solid                                                                     82   Hygroscopic                                                                               463(M.sup.+ --HCl), 168(100%)                                                                      3                                               solid                                                                     83   121˜123                                                                             459(M.sup.+), 380(100%)                                                                            1                                          84   154˜156                                                                             473(M.sup.+), 394(100%)                                                                            1                                          85   203˜205                                                                             see Example 3       3                                          86   133˜134                                                                             588(M.sup.+), 278(100%)                                                                            4                                          87   95˜96                                                                               616(M.sup.+), 180(100%)                                                                            4                                          88   106˜107                                                                             528(M.sup.+ --Q83), 154(100%)                                                                      1                                          89   211˜212                                                                             410(M.sup.+), 92(100%)                                                                             2                                          90   152˜154                                                                             429(M.sup.+), 151(100%)                                                                            1                                          91   134˜135                                                                             370(M.sup.+), 91(100%)                                                                             1                                          92   190˜202                                                                             370(M.sup.+ --HCl), 91(100%)                                                                       3                                          93   166˜172                                                                             370[M.sup.+ --(CH--CO.sub.2 H).sub.2 ],                                                            6                                                          91(100%)                                                       94   105˜106                                                                             380, 182(100%)      1                                          95   145.5˜146                                                                           211(100%), 141      1                                          96   155˜156                                                                             276, 211(100%)      1                                          97   169˜170                                                                             296, 211(100%)      1                                          98     132˜132.5                                                                         515(M.sup.+ --Br), 170(100%)                                                                       1                                          99   149˜150                                                                             535(M.sup.+), 170(100%)                                                                            1                                         100   142˜143                                                                             211(100%), 141      1                                         101   130˜133                                                                             414(M.sup.+), 91(100%)                                                                             1                                         102   118˜119                                                                             428(M.sup.+), 91(100%)                                                                             1                                         103   146˜147                                                                             408(M.sup.+ --Br), 151(100%)                                                                       1                                         104   203˜205                                                                             471(M.sup.+), 106(100%)                                                                            1                                         105   153.5˜154                                                                           404(M.sup.+), 125(100%)                                                                            1                                         106   148˜150                                                                             448(M.sup.+), 151(100%)                                                                            1                                         107   188˜190                                                                             see Example 7       7                                         108   156.5˜157                                                                           480(M.sup.+), 126(100%)                                                                            1                                         109   142˜143                                                                             522(M.sup.+), 126(100%)                                                                            1                                         110   139.5˜140                                                                           421(M.sup.+), 126(100%)                                                                            1                                         111   173˜174                                                                             435(M.sup.+), 140(100%)                                                                            1                                         112   142.5˜144                                                                           494(M.sup.+), 140(100%)                                                                            1                                         113   209˜214                                                                             485(M.sup.+ --HCl), 190(100%)                                                                      3                                         114   173˜175                                                                             296[M.sup.+ --(CH.sub.2).sub.3 CONHPh],                                                            4                                                          161(100%)                                                     115   218.5˜219                                                                           205[M.sup.+ --((CH.sub.2).sub.3 CON--Q96,                                                          4                                                          CH.sub.2 --Q23)], 151(100%)                                   116   233˜234                                                                             205[M.sup.+ --(CH.sub.2).sub.3 CONH--Q97],                                                         4                                                          151(100%)                                                     117     216˜216.5                                                                         551(M.sup.+), 151(100%)                                                                            4                                         118   132˜134                                                                             437(M.sup.+), 142(100%)                                                                            4                                         119   131˜132                                                                             505(M.sup.+), 210(100%)                                                                            4                                         120   129˜130                                                                             354[M.sup.+ --(CH.sub.2).sub.3 CONMe--Q2],                                                         4                                                          151(100%)                                                     121    97˜104                                                                             499(M.sup.+ --HCl), 204(100%)                                                                      3                                         122   141˜144                                                                             392(M.sup.+ --Br), 76(100%)                                                                        4                                         123   105˜110                                                                             513(M.sup.+ --HCl), 218(100%)                                                                      3                                         124   153˜155                                                                             485(M.sup.+), 190(100%)                                                                            4                                         125   110˜111                                                                             572(M.sup.+ ), 218(100%)                                                                           4                                         126   186˜193                                                                             479(M.sup.+ --HCl), 184(100%)                                                                      3                                         127   199˜201                                                                             451(M.sup.+), 156(100%)                                                                            4                                         128     176˜176.5                                                                         568(M.sup.+), 258(100%)                                                                            4                                         129   145˜147                                                                             471(M.sup.+), 105(100%)                                                                            1                                         130   164˜165                                                                             530(M.sup.+), 151(100%)                                                                            4                                         131   101˜103                                                                             463(M.sup.+), 98(100%)                                                                             1                                         132   137˜140                                                                             449(M.sup.+), 98(100%)                                                                             1                                         133     152˜152.5                                                                         522(M.sup.+), 151(100%)                                                                            1                                         134     123˜123.5                                                                         477(M.sup.+), 398(100%)                                                                            1                                         135   Amorphous  463(M.sup.+ --HCl), 168(100%)                                                                      3                                         136   142˜143                                                                             459(M.sup.+), 45(100%)                                                                             1                                         137   129.5˜131                                                                           522(M.sup.+), 168(100%)                                                                            1                                         138     192˜193.5                                                                         431(M.sup.+), 136(100%)                                                                            1                                         139     119˜119.5                                                                         439(M.sup.+ --Br), 151(100%)                                                                       1                                         140   168˜170                                                                             490(M.sup.+), 151(100%)                                                                            1                                         141   192.5˜194                                                                           493(M.sup.+), 198(100%)                                                                            1                                         142   103˜109                                                                             521(M.sup.+), 184(100%)                                                                            1                                         143   164˜165                                                                             473(M.sup.+ --Br), 151(100%)                                                                       1                                         144   142˜143                                                                             501(M.sup.+ --Br), 151(100%)                                                                       1                                         145   168˜ 169                                                                            445(M.sup.+), 122(100%)                                                                            1                                         146   107˜108                                                                             473(M.sup.+), 98(100%)                                                                             1                                         147   179˜180                                                                             504(M.sup.+), 151(100%)                                                                            1                                         148   138.5˜139                                                                           453(M.sup.+ --Br), 151(100%)                                                                       1                                         149     139˜139.5                                                                         393(M.sup.+ --OMe), 98(100%)                                                                       1                                         150   134˜136                                                                             439(M.sup.+), 92(100%)                                                                             1                                         151   190˜191                                                                             411(M.sup.+), 116(100%)                                                                            1                                         152   153˜154                                                                             484(M.sup.+), 151(100%)                                                                            1                                         153   97˜99                                                                               498(M.sup.+), 151(100%)                                                                            1                                         154   107˜108                                                                             439(M.sup.+), 144(100%)                                                                            1                                         155   102.5˜104                                                                           453(M.sup.+), 102(100%)                                                                            1                                         156   122˜123                                                                             425(M.sup.+), 130(100%)                                                                            1                                         157   106.5˜107                                                                           498(M.sup.+), 151(100%)                                                                            1                                         158   134.5˜136                                                                           512(M.sup.+), 151(100%)                                                                            1                                         159     123˜124.5                                                                         451(M.sup.+), 100(100%)                                                                            1                                         160   129˜130                                                                             465(M.sup.+), 386(100%)                                                                            1                                         161   Oily       437(M.sup.+), 142(100%)                                                                            1                                               substance                                                                162   139˜140                                                                             524(M.sup.+), 151(100%)                                                                            1                                         163     133˜134.5                                                                         496(M.sup.+), 151(100%)                                                                            1                                         164   135˜142                                                                             395[M.sup.+ --(NHPh, HCl)],                                                                        3                                                          119(100%)                                                     165   170˜177                                                                             398[M.sup.+ --(CONHPh, HCl)],                                                                      3                                                          119(100%)                                                     166   188˜205                                                                             448(M.sup.+ --HCl), 151(100%)                                                                      3                                         167   184˜190                                                                             404(M.sup.+ --HCl), 125(100%)                                                                      3                                         168   153˜156                                                                             418(M.sup.+), 125(100%)                                                                            1                                         169   160˜161                                                                             448[M.sup.+ --(CH--CO.sub.2 H).sub.2 ],                                                            6                                                          151(100%)                                                     170   155˜156                                                                             448[M.sup.+ --1/2(HC(OH)CO.sub.2 H).sub.2 ],                                                       6                                                          151(100%)                                                     171   163˜165                                                                             448[M.sup.+ --1/2(CH--CO.sub.2 H).sub.2 ],                                                         6                                                          151(100%)                                                     172   178.5˜179.5                                                                         448[M.sup.+ --1/2(CO.sub.2 H).sub.2 ],                                                             651(100%)                                 173   112˜114                                                                             444(M.sup.+), 148(100%)                                                                            1                                         174   130˜131                                                                             458(M.sup.+), 121(100%)                                                                            1                                         175   103˜105                                                                             472(M.sup.+), 121(100%)                                                                            1                                         176   124˜126                                                                             428(M.sup.+), 121(100%)                                                                            1                                         177   150˜152                                                                             424(M.sup.+ --Br), 151(100%)                                                                       1                                         178   152˜154                                                                             487(M.sup.+ --Br), 184(100%)                                                                       1                                         179   103˜105                                                                             539(M.sup.+), 132(100%)                                                                            1                                         180   147˜151                                                                             460(M.sup.+), 164(100%)                                                                            1                                         181   205˜215                                                                             476(M.sup.+ --HCl), 217(100%)                                                                      1                                         182   129˜131                                                                             474(M.sup.+), 178(100%)                                                                            1                                         183   169˜170                                                                             533(M.sup.+), 151(100%)                                                                            1                                         184   126˜127                                                                             502(M.sup.+), 164(100%)                                                                            1                                         185   109˜111                                                                             561(M.sup.+), 151(100%)                                                                            1                                         186   131˜132                                                                             502(M.sup.+), 164(100%)                                                                            1                                         187   103˜105                                                                             561(M.sup.+), 151(100%)                                                                            1                                         188   188˜190                                                                             460(M.sup.+), 164(100%)                                                                            1                                         189   163.5˜164                                                                           519(M.sup.+), 151(100%)                                                                            1                                         190   85.5˜86                                                                             444(M.sup.+), 148(100%)                                                                            1                                         191   187˜188                                                                             472(M.sup.+), 147(100%)                                                                            1                                         192     149˜150.5                                                                         561(M.sup.+), 151(100%)                                                                            1                                         193   206˜210                                                                             420(M.sup.+ --HCl), 97(100%)                                                                       3                                         194   209˜210                                                                             420(M.sup.+), 97(100%)                                                                             1                                         195   138˜142                                                                             479(M.sup.+), 151(100%)                                                                            1                                         196   143˜145                                                                             415(M.sup.+), 336(100%)                                                                            1                                         197   152.5˜153                                                                           474(M.sup.+), 151(100%)                                                                            1                                         198   91˜96                                                                               416(M.sup.+), 337(100%)                                                                            1                                         199     168˜168.5                                                                         475(M.sup.+), 151(100%)                                                                            1                                         200     134˜134.5                                                                         405(M.sup.+), 92(100%)                                                                             1                                         201   130.5˜131                                                                           464(M.sup.+), 151(100%)                                                                            1                                         202   116˜126                                                                             452(M.sup.+), 151(100%)                                                                            3                                         203   110˜120                                                                             442(M.sup.+), 58(100%)                                                                             3                                         204   179˜184                                                                             454(M.sup.+ --HCl), 86(100%)                                                                       3                                         205   115˜120                                                                             571(M.sup.+), 151(100%)                                                                            3                                         206   127˜132                                                                             605(M.sup.+), 151(100%)                                                                            3                                         207   160˜168                                                                             567(M.sup.+ --Br), 151(100%)                                                                       3                                         208   150˜151                                                                             413(M.sup.+), 135(100%)                                                                            1                                         209   144˜146                                                                             464(M.sup.+), 135(100%)                                                                            1                                         210   162˜163                                                                             428(M.sup.+), 91(100%)                                                                             1                                         211   181˜182                                                                             427(M.sup.+), 135(100%)                                                                            1                                         212   145˜146                                                                             519(M.sup.+), 135(100%)                                                                            1                                         213   156˜165                                                                             589(M.sup.+), 135(100%)                                                                            3                                         214   176˜179                                                                             252[M.sup.+ --CH.sub.2 C(Me.sub.2)CH.sub.2 --Q2],                                                  3                                                          125(100%)                                                     215   167˜168                                                                             392(M.sup.+ --Br), 135(100%)                                                                       1                                         216   190˜192                                                                             447(M.sup.+), 135(100%)                                                                            1                                         217   Oily       441(M.sup.+), 135(100%)                                                                            8                                               substance                                                                218   97˜98                                                                               455(M.sup.+), 135(100%)                                                                            8                                         219   147˜148                                                                             418(M.sup.+), 135(100%)                                                                            1                                         220   174˜177                                                                             462(M.sup.+ ), 125(100%)                                                                           1                                         221   131˜132                                                                             482(M.sup.+), 125(100%)                                                                            1                                         222   151˜153                                                                             432(M.sup.+), 155(100%)                                                                            1                                         223   141˜144                                                                             438(M.sup.+), 81(100%)                                                                             1                                         224   168˜169                                                                             418(M.sup.+ --Br)(100%)                                                                            1                                         225   149˜152                                                                             461(M.sup.+), 382(100%)                                                                            1                                         226   Oily       521(M.sup.+), 151(100%)                                                                            8                                               substance                                                                227   140˜141                                                                             see Example 9       9                                         228     108˜108.5                                                                         515(M.sup.+), 193(100%)                                                                            1                                         229   203˜205                                                                             471(M.sup.+), 106(100%)                                                                            1                                         230   191˜192                                                                             see Example 10      10                                        231   123˜125                                                                             521(M.sup.+), 105(100%)                                                                            1                                         232   112˜113                                                                             549(M.sup.+), 471(100%)                                                                            1                                         233   113˜115                                                                             549(M.sup.+), 471(100%)                                                                            1                                         234   146˜147                                                                             408(M.sup.+), 151(100%)                                                                            1                                         235   178˜181                                                                             492(M.sup.+), 121(100%)                                                                            1                                         236   178˜181                                                                             527(M.sup.+), 171(100%)                                                                            1                                         237   185˜189                                                                             399(M.sup.+ --Br), 122(100%)                                                                       1                                         238   Oily       see Example 8       8                                               substance                                                                239   153˜154                                                                             428(M.sup.+ --Br), 151(100%)                                                                       1                                         240   Oily       518(M.sup.+ --Br), 105(100%)                                                                       1                                               substance                                                                ______________________________________                                    

FORMULATION EXAMPLE 1 (Tablets)

    ______________________________________                                         Compound No. 85       10 g                                                     Lactose               20 g                                                     Starch                 4 g                                                     Starch for paste       1 g                                                     Magnesium stearate    0.1 g                                                    Carboxymethyl cellulose calcium                                                                       7 g                                                     Total                 42.1 g                                                   ______________________________________                                    

The above components were mixed in a usual manner, and formulated into sugar-coated tablets each containing 50 mg of an active ingredient.

FORMULATION EXAMPLE 2 (Capsules)

    ______________________________________                                         Compound No. 88    10 g                                                        Lactose            20 g                                                        Microcrystal cellulose                                                                            10 g                                                        Magnesium stearate  1 g                                                        Total              41 g                                                        ______________________________________                                    

The above components were mixed in a usual manner, and filled into gelatin capsules to obtain capsules each containing 50 mg of an active ingredient.

FORMULATION EXAMPLE 3 (Soft capsules)

    ______________________________________                                         Compound No. 94  10 g                                                          Corn oil         35 g                                                          Total            45 g                                                          ______________________________________                                    

The above components were mixed and formulated in a usual manner to obtain soft capsules.

FORMULATION EXAMPLE 4 (Ointment)

    ______________________________________                                         Compound No. 55  1.0 g                                                         Olive oil        20 g                                                          White vaseline   79 g                                                          Total            100 g                                                         ______________________________________                                    

The above components were mixed in a usual manner to obtain 1% ointment.

FORMULATION EXAMPLE 5 (Aerosol suspension)

    ______________________________________                                         (A)     Compound No. 11    0.25%                                                       Isopropyl myristate                                                                               0.10%                                                       Ethanol            26.40%                                              (B)     A 60-40% mixture of 1,2-                                                                          73.25%                                                      dichlorotetrafluoroethane and                                                  1-chloropentafluoroethane                                              ______________________________________                                    

The above composition (A) was mixed. The solution mixture thereby obtained was charged in a container equipped with a valve, and the propellant (B) was injected from the valve nozzle to a gauge pressure of from about 2.46 to 2.81 mg/cm² to obtain an aerosol suspension.

Test Method

I. Anti-platelet aggregation effect

1. In vitro test

(A) Anti-platelet aggregation effect in rabbits

Blood was collected from the central artery of Japanese white male rabbits (weight: 1.8 to 2.5 kg) into a syringe containing 1/10 volume 3.8% sodium citrate. The blood thus obtained was subjected to a centrifuge at 200× g for 7 minutes at room temperature to obtain platelet rich plasma (PRP). Furthermore, the residue was subjected to a centrifuge at 2000× g for 10 minutes to obtain platelet poor plasma (PPP). The measurement was effected by diluting PRP and PPP to 300,000/m³. PRP and PPP were placed in a cuvette, and the measurement range of transmittance was adjusted to 0% in the case of PRP and to 100% in the case of PPP. Thereafter, a test sample drug dissolved in 100% dimethylsulfoxide (DMSO) was added to PRP (the final concentration of DMSO: 0.25%). After incubation was effected at 37° C., 900 rpm for 2 minutes, an aggregating agent was added to measure an aggregation curve. The anti-platelet aggregation effect of the test sample drug was expressed by a concentration (IC₅₀ : μM) at which the aggregation of control sample was 50% inhibited. The aggregating agents ADP and arachidonic acid (A.A) were used at minimum concentrations (ADP: 5 to 10 μM: A.A.: 0.2 to 0.3 mM) which caused maximum aggregation. The measurement of platelet aggregation was carried out by using NBS HEMA TRACER 601.

(B) Anti-platelet aggregation effect in guinea-pigs

Blood was collected from the central artery of a Hartley type male guinea-pig (weight: about 300 g) in the same manner as above, and was subjected to a centrifuge at 160× g for 10 minutes at room temperature to obtain PRP. Furthermore, the residue was subjected to a centrifuge at 3000×g for 15 minutes. PRP for measurement was prepared in the same manner as in the above rabbit test example, and a test sample drug dissolved in 100% DMSO was added (DMSO final concentration: 0.5%) to calculate 50% aggregation-inhibiting concentration IC₅₀ value to a control sample. As the aggregating agent, A.A having the final concentration of 0.2 mM was used.

2. In vivo test

(A) Anti-platelet aggregation effect in rabbits

After a Japanese white male rabbit (weight: 1.8 to 2.5 kg) was fasted for 18 hours, a test sample drug suspended in 0.5% methyl cellulose was orally administered thereto. After administration, blood was periodically collected from ear artery, and PRP was prepared in the same manner as in the above in vitro test to measure platelet aggregation caused by each aggregating agent. The effect of the test sample drug was evaluated by inhibited aggregation ratio calculated on the assumption that the aggregation before administration was 100%.

(B) Anti-platelet aggregation effect on guinea-pigs

(1) After a Hartley type male guinea-pig (weight: around 350 g) was fasted for 18 hours, a test sample drug suspended in a 5% gum arabic solution was orally administered thereto. After administration, blood was collected periodically from central artery, and PRP was prepared in the same manner as in the above in vitro test to measure platelet aggregation caused by each aggregating agent. The effect of the test sample drug was evaluated by inhibited aggregation ratio calculated on the assumption that the aggregation before administration was 100%.

(2) After a Hartley type male guinea-pig (weight: around 350 g) was fasted for 18 hours, a test sample drug suspended in a 5% gum arabic solution was orally administered thereto. One hour after the administration, blood was collected from central artery, and PRP was prepared in the same manner as in the above in vitro test to measure platelet aggregation caused by each aggregating agent. The effect of the test sample drug was evaluated by inhibited aggregation ratio calculated on the assumption that the aggregation before administration was 100%.

(C) Thrombocytopenia model of mouse

Collagen (Hormon-Chemie Co., Ltd.) diluted in an isotonic sodium chloride solution was administered to an ICR male mouse (weight: 24-30 g) through the tail vein in an amount of 1 mg/5 ml/kg. Five minutes later, under pentobarbital anesthesia, 9 volume amounts of blood was collected from inferier vena cava into a plastic syringe containing one volume amount of 3.8% sodium citrate. A test sample drug was orally administered one hour before the administration of collagen. The blood thus collected was diluted 20 times with Isotone II, and was subjected to a centrifuge at 60× g for 5 minutes. Thereafter the upper layer was further diluted with Isotone II to measure the number of platelets by a coulter counter (model ZM).

In the above tests I-1 and I-2, ticlopidine hydrochloride (Daiichi Seiyaku Co., Ltd.) and Cilostazol (Otsuka Pharmaceutical Co., Ltd.) were used as control drugs.

II. Cardiotonic effect

After exsanguinating a male guinea-pig (Hartley type, 250-400 g), the heart was taken out and was immediately dipped in a nutrition solution (Kreb's-Henseleit solution: NaCl 118.4 mM, KCl 4.7 mM, MgSO₄.7 H₂ O 1.18 mM, CaCl₂.2 H₂ O 2.5 mM, KH₂ PO₄ 1.2 mM, NaHCO₃ 24.9 mM, Glucose 11.1 mM) aerated with oxygen (containing 5% of carbon dioxide). Thereafter, the oxygen-aerated nutrition solution was placed in a laboratory dish for preparing a sample, and oxygen was continuously aerated. After rapidly separating the atrium and the ventricle, a papillary muscle sample was prepared from the right ventricle, and was suspended in an organ bath filled with the oxygen-aerated nutrition solution maintained at 31° C., the 500 mg of tension being loaded thereto.

After suspending the papillary muscle sample, the nutrition solution was replaced 20 minutes later and 40 minutes later, and after observing for further 20 minutes, isoproterenol was accumulatively administered (the final concentration: 3×10⁻⁷ M) to observe the effect on the contractile force. After repeating the procedure after suspending once more in the same manner as above, the nutrition solution was replaced 20 minutes later and 40 minutes later, and after observing for further 20 minutes, a test sample drug was accumulatively administered. The effect of each test sample drug on contractile force was evaluated by change ratio (%) caused by the test sample drug on the assumption that the difference in contractile force at the second isoproterenol administration was 100%, and a concentration EC₃₀ (μM) necessary for making 30% increase was calculated.

The measurement of contractile force was conducted by applying rectangular pulses [voltage: threshold value ×2 (V), duration: 3 (msec), frequency: 1 (Hz)] onto the papillary muscle through bipolar platinum electrodes by an electronic stimulator (Nihon Kohden SEN-3201) to record the generated tension on a recorder by a F-D pickup and strain gage.

As a control cardiotonics, a Milrinone (Winthrop Co.) was used.

III. Vasodilatory effect

A male rabbit (Japanese white type, 2-2.5 kg) was subjected to anesthesia by intravenous injection of nembutal [weight (kg)×0.5+0.5 ml]. After exsanguination, the thoracic aorta was taken out and was immediately dipped in a nutrition solution (Kreb's-Henseleit solution: NaCl 118.4 mM, KCl 4.7 mM, MgSO₄.7H₂ O 1.188 mM, CaCl₂.2H₂ O 2.5 mM, KH₂ PO₄ 1.2 mM, NaHCO₃ 24.9 mM, Glucose 11.1 mM) aerated with oxygen (containing 5% of carbon dioxide). Thereafter, it was placed in a laboratory dish for preparing a sample, which was filled with the oxygen-aerated nutrition solution, and both ends of the blood vessel were fixed by pins to remove fat and connective tissue. A spiral sample (width: 3 mm, length: about 1 cm) was prepared by cutting with scissors. The both sides of the sample was fixed by a clip, and was suspended in an organ bath filled with the oxygen-aerated nutrition solution and maintained at 37° C., then a tension of 2 g being loaded thereon.

The tension of the blood vessel was recorded on a recorder (Nihon Kohden) by means of an F-D pickup (Nihon Kohden 611-T) and strain gage (Nihon Kohden AP-600G).

After suspending, the nutrition solution was replaced 20 minutes later and 40 minutes later, and each sample was observed for further 20 minutes (during which the tension was maintained 2 g). Thereafter, norepinephrine was administered (final concentration: 10⁻⁶ M) and the blood vessel influenced by tension was observed. After the contraction became stable, the nutrition solution was replaced, and the nutrition solution was further replaced 20 minutes later and 40 minutes later. After observing for further 20 minutes, the blood vessel was contracted by a contractile agent. After the contraction became stable, a test sample drug was accumulatively administered. After finishing the test, papaverine was administered (final concentration: 10⁻⁴ M) to achieve complete relaxation.

The effect of the test sample drug on contraction by the contractile agent was evaluated by a change ratio (%) caused by the test sample drug on the assumption that the difference in tension between at the time of administration of the contractile agent and after the administration of papaverine was 100%.

IV. Anti-SRS-A effect (bronchodilating effect)

Drug:

A test sample drug was used by dissolving and diluting in 100% dimethylsulfoxide (DMSO, Wako Junyaku). Leukotriene D₄ (LTD₄, Ultrafine) was diluted with distilled water.

Indomethacin (Indo, Sigma) was dissolved in 100% ethanol (EtOH, Komune Kagaku). Aminophylline (AP, Sigma), histamine dihydrochloride (His, Wako Junyaku) was dissolved in distilled water. The final concentrations of DMSO and EtOH in a bath were made respectively not higher than 0.25% v/v and not higher than 0.1% v/v.

Method:

A guinea-pig of 300-450 g was exsanguinated, and the trachea was taken out. After removing fat and connective tissue, it was cut into spiral strips having a width of about 2 mm and was divided into 2 to 3 pieces, each containing 4 smooth muscle tissues. The sample thus prepared was suspended in an organ bath of 8 ml containing a modified Tyrode solution aerated with 95% O₂ +5% CO₂ at 37° C., and 1 g of load was applied thereon. The relaxation of the muscle was recorded by a pen recorder (Yokogawa Hokushin Electric, type 3066) by means of an isotonic transducer (Nihon Kohden, TD-112S).

The composition of the modified Tyrode solution was as follows (mM):

NaCl 137, KCl 2.7, CaCl₂ 1.8, MgCl₂ 1.0, NaHCO₃ 20, NaH₂ PO₄ 0.32, Glucose 11.

The sample was allowed to stand for 50-60 minutes, and was contracted with histamine dihydrochloride (100 μM). After the reaction became constant, it was washed and allowed to stand for 20-30 minutes. Indomethacin (5 μM) was added to the sample, and after incubation for 30 minutes, the sample was contracted by adding LTD₄ (30 nM). After the reaction became stable, a test drug was accumulatively administered. Finally AP (1 mM) was added to achieve maximum relaxtant reaction. The result was expressed by relaxation percent on the assumption that the relaxation by AP was 100%, and a concentration to achieve 50% relaxation (EC₅₀, μM) was measured.

As a control drug, FPL-55712 recognized as a selective SRS-A antagonistic agent was used [(Fisons Ltd.); Journal of Medicinal Chemistry, Vol 20, pp. 371-379, 1977].

Test results:

I Anti-platelet aggregation effect

1. In vitro test: (A), (B)

Tables III-1 to III-3 show anti-platelet aggregation effects of test compounds evaluated as IC₅₀ values (μM).

                  TABLE III-1                                                      ______________________________________                                                         Rabbit PRP; IC.sub.50                                          Test Compound No. ADP      A.A.                                                ______________________________________                                         1                  0.22    0.5                                                 Cilostazol        28.0     8.8                                                 ______________________________________                                    

                  TABLE III-2                                                      ______________________________________                                         Test      Rabbit PRP  Test        Rabbit PRP                                   Compound No.                                                                             ADP; IC.sub.50                                                                             Compound No.                                                                               ADP; IC.sub.50                               ______________________________________                                          9        0.32        143         0.25                                         11        0.85        153         0.61                                         12        0.93        158         0.22                                         13        0.52        162          0.053                                       21        6.0         166         0.14                                         26        0.16        167         0.14                                         27        0.24        169          0.064                                       29        0.58        173         0.15                                         30        0.29        177          0.042                                       36        0.45        178         0.1                                          38        0.52        180         0.12                                         42        18.0        183         0.03                                         47        0.05        181          0.024                                       48        0.15        188         0.24                                         54        2.7         190         0.29                                         61        0.19        192          0.081                                       70        0.43        195         0.48                                         76        1.2         199         0.72                                         85        0.10        206         0.64                                         86        0.33        210         0.14                                         120       0.6         230         0.18                                         133       0.18        239         0.16                                         137       0.13        Cilostazol  28.0                                         ______________________________________                                    

                  TABLE III-3                                                      ______________________________________                                                         Guinea-pig PRP                                                 Test Compound No.                                                                              A.A.; IC.sub.50                                                ______________________________________                                         85              0.026                                                          88              0.018                                                          94              0.018                                                          99              0.18                                                           Cilostazol      1.4                                                            ______________________________________                                    

2. in vivo test

(A) Anti-platelet aggregation effect in rabbits

                  TABLE III-4                                                      ______________________________________                                                  Adminis-           Aggre-                                                                               Average ratio of                             Test     tration            gation-                                                                              anti-platelet                                Compound amount   Example   causing                                                                              aggregation (%)                              No.      (mg/kg)  number    agent 1 hr. 3 hrs.                                 ______________________________________                                         72       50       2         ADP   57    59                                     72       50       2         A.A.  98    86                                     75       50       2         ADP   65    31                                     75       50       2         A.A.  76    21                                     Ticlopidine                                                                             300      3         ADP   24    36                                     hydrochloride                                                                  Ticlopidine                                                                             300      3         A.A.  13     2                                     hydrochloride                                                                  ______________________________________                                    

(B) Anti-platelet aggregation effect in guinea-pigs (1)

                  TABLE III-5                                                      ______________________________________                                                  Adminis-           Aggre-                                                                               Average ratio of                             Test     tration            gation-                                                                              anti-platelet                                Compound amount   Example   causing                                                                              aggregation (%)                              No.      (mg/kg)  number    agent 1 hr. 3 hrs.                                 ______________________________________                                         166      10       3         A.A.  85    59                                     181      30       1         A.A.  69    71                                     158      30       1         A.A.  68    35                                     ______________________________________                                    

Anti-platelet aggregation effect in guinea pigs (2)

                  TABLE III-6                                                      ______________________________________                                         Test    Administration                                                                             Aggregation-                                                                              Ratio of anti-                                  Compound                                                                               amount      causing    platelet aggregation                            No.     (mg/kg)     agent      (%)                                             ______________________________________                                          85      3          A.A.       57.8                                             92     10          A.A.       92.5                                            152     10          A.A.       93.1                                            166      3          A.A.       93.1                                            181     10          A.A.       88.6                                            169     10          A.A.       92.7                                            ______________________________________                                    

(C) Effect of inhibiting reduction in platelets of mice

                  TABLE III-7                                                      ______________________________________                                         Test      Administration        Average inhibit-                               Compound  amount      Example   ing ratio                                      No.       (mg/kg)     number    (%)                                            ______________________________________                                         38        30          5         31.4*                                          52        30          5         51.1*                                          84        10          5          55.0**                                        85        30          5         36.6*                                          Ticlopidine                                                                              300         6         30.1                                           hydrochloride                                                                  Ticlopidine                                                                              100         6         13.7                                           hydrochloride                                                                  Cilostazol                                                                               100         5         39.4*                                          Cilostazol                                                                               30          6         18.3                                           ______________________________________                                          *1: Significant difference from control value was statistically recognize      at the ratio of risk of 5% (* mark) and at the ratio of risk of 1% (**         mark).                                                                   

II. Cardiotonic effect

                  TABLE IV                                                         ______________________________________                                         Test        Contractile                                                                               Maximum reaction                                        Compound    force of heart                                                                            ratio                                                   No.         EC.sub.30 (μM)                                                                         % (μM)                                               ______________________________________                                         11          11.2       57.7(300)                                               44          20.6       51.0(300)                                               Milrinone   33.9       59.1(300)                                               ______________________________________                                          *.sup.2 : Maximum contractile force is expressed by reaction rate to           contractile force of isoproterenol, and numerical value in parenthesis         indicates minimum concentration (measured at 300 μM) at that time.    

III. Vasodilatory effect

                  TABLE V                                                          ______________________________________                                                 Vasodilatory                                                           Test      effect        EC.sub.30 (μM)                                      Compound  NE*.sup.3     U-46619  PGF.sub.2 α                             No.       10.sup.-6 M   10.sup.-7 M                                                                             10.sup.-6 M                                   ______________________________________                                         11        0.363         2.19     0.447                                         Papaverine                                                                               4.37          10.5     8.71                                          ______________________________________                                          *.sup.3 NE = norepinephrine                                              

IV. Anti-SRS-A effect

                  TABLE VI                                                         ______________________________________                                         Test                   Test                                                    Compound No.                                                                               EC.sub.50  Compound No.                                                                               EC.sub.50                                   ______________________________________                                         12           0.023     55          0.068                                       13          0.40       75          0.21                                        16          0.28       84          0.025                                       21          0.26       94          0.059                                       23          0.23       96          0.56                                        28          0.42       FPL-55712   0.10                                        ______________________________________                                    

INDUSTRIAL APPLICABILITY

As evident from the above results, it is clear that the compound of the present invention has excellent anti-platelet aggregation effect, cardiotonic effect, vasodilatory effect and anti-SRS-A effect. Thus, the compound of the present invention can be useful prophylactic and therapeutic drugs for various thrombotic diseases, congestive heart failure, hypertension, angina pectoris, and immediate type allergy diseases including asthma. 

We claim:
 1. A 3(2H)-pyridazinone of the formula: ##STR50## wherein R¹ is a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₃ -C₄ alkenyl group or (CH₂)_(n) CO₂ R⁵, where n is an integer from 1 to 4, R⁵ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group;R² is A¹ -Y¹, where A¹ is a straight chain or branched C₁ -C₁₂ alkylene group, Y¹ is an unsubstituted thienyl or pyridyl group which is unsubstituted or substituted on nitrogen by oxygen or on carbon by a halogen or C₁ -C₃ alkoxy group; R³ and R⁴ are independently a hydrogen atom or a straight chain or branched C₁ -C₃ alkyl group; X is a chlorine atom, a bromine atom, a hydrogen atom or a cyano group; and Ar is ##STR51## where R²¹ is a hydrogen atom or OR⁵, where R⁵ is as defined above, or ##STR52## where Z² and Z³ are independently a hydrogen atom, a halogen atom, a straight chain or branched C₁ -C₄ alkyl group, OR²², where R²² is a hydrogen atom or a straight chain or branched C₁ -C₈ alkyl group, or O--A¹ --Y³, where A¹ is as defined above and Y³ is a phenyl group which is unsubstituted or substituted with a straight chain or branched C₁ -C₄ alkyl group or a halogen atom, CO₃ R⁵, where R⁵ is as defined above, or ##STR53## where R⁷ and R⁸ are independently a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, a C₃ -C₈ cycloalkyl group, a phenyl group or an unsubstituted thiazolyl or thiadiazolyl group, or R⁷ and R⁸ together form a C₂ -C₈ alkylene group which is unsubstituted or substituted with a straight chain or branched C₁ -C₃ alkyl group or a phenyl group, or form a morpholine ring with a nitrogen atom, or Z² and Z³ together with a benzene ring, form ##STR54## where W is C₁ -C₈ alkylene group which is unsubstituted or substituted with a straight chain C₁ -C₃ alkyl group; or a pharmaceutically acceptable salt thereof.
 2. A 3(2H)-pyridazinone compound according to claim 1, wherein R⁴ is a hydrogen atom and X is a chlorine atom, a bromine atom or a cyano group; and a pharmaceutically acceptable salt thereof.
 3. A 3(2H)-pyridazinone compound according to claim 2 of the formula: ##STR55## wherein R¹ is a hydrogen atom, a straight chain or branched C₁ -C₄ alkyl group, or (CH₂)_(n) CO₂ R⁴, where n is an integer from 1 to 4, R⁴ is a hydrogen atom or a straight chain or branched C₁ -C₄ alkyl group;R² is A¹ --Y¹, where A¹ is a straight chain or branched C₁ -C₁₂ alkylene group, Y¹ is an unsubstituted thienyl or pyridyl group which is unsubstituted or substituted on nitrogen by oxygen or on carbon by a halogen or C₁ -C₃ alkoxy group; R³ is a hydrogen atom or a straight chain or branched C₁ -C₃ alkyl group; X is a chlorine atom, a bromine atom, or a cyano group; and Ar is ##STR56## where R¹⁹ is a hydrogen atom or OR⁴, where R⁴ is as defined above, or ##STR57## where Z² and Z³ are independently a hydrogen atom, a halogen atom, a straight chain or branched C₁ -C₄ alkyl group, OR²⁰, where R²⁰ is a hydrogen atom or a straight chain or branched C₁ -C₈ alkyl group, or O--A³ --Y³, where A³ is a C₁ -C₄ alkylene group, and Y³ is a phenyl group, CO₂ R⁴, where R⁴ is as defined above, or ##STR58## where R²¹ and R²² are independently a straight chain or branched C₁ -C₄ alkyl group, a C₃ -C₇ cycloalkyl group, or R²¹ and R²² together form a C₂ -C₆ alkylene group, or Z² and Z³ together with a benzene ring, form ##STR59## where W is C₁ -C₂ alkylene group; and a pharmaceutically acceptable salt thereof.
 4. A 3(2H)-pyridazinone compound and the pharmaceutically acceptable salt thereof according to claim 3, wherein R¹ and R³ are hydrogen atoms.
 5. An anti-thrombotic, inotropic, vasodilatory, or anti-SRS-A agent comprising an effective amount of the 3(2H)-pyridazinone compound or its pharmaceutically acceptable salt as defined in claim 1 in combination with a pharmaceutically acceptable carrier therefor. 